Ethenyl-substituted pyridine and pyrimidine derivatives and their use in treating viral infections

ABSTRACT

The present invention provides compounds of Formula (A): (Chemical formula should be inserted here as it appears on abstract in paper form) (A) and tautomers, isomers, and esters of said compounds, and pharmaceutically acceptable salts, solvates, and prodrugs of said compounds, wherein wherein each of R, R 1 , X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 18 , R 19 , R 22 , R 23 , and n is selected independently and as defined herein. Compositions comprising such compounds are also provided. The compounds of the invention are effective as inhibitors of HCV, and are useful, alone and together with other therapeutic agents, in treating or preventing diseases or disorders such as viral infections and virus-related disorders.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to provisional application U.S. Ser.No. 61/090,455, filed Aug. 20, 2008, incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to certain ethenyl-substituted pyridineand pyrimidine derivatives, to compositions comprising them, and tomethods for their use as inhibitors of HCV and in treating or preventingviral infections or virus-related disorders.

BACKGROUND OF THE INVENTION

HCV is a (+)-sense single-stranded RNA virus that has been implicated asthe major causative agent in non-A, non-B hepatitis (NANBH). NANBH isdistinguished from other types of viral-induced liver disease, such ashepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis delta virus(HDV), as well as from other forms of liver disease such as alcoholismand primary biliary cirrhosis.

Hepatitis C virus is a member of the hepacivirus genus in the familyFlaviviridae. It is the major causative agent of non-A, non-B viralhepatitis and is the major cause of transfusion-associated hepatitis andaccounts for a significant proportion of hepatitis cases worldwide.Although acute HCV infection is often asymptomatic, nearly 80% of casesresolve to chronic hepatitis. About 60% of patients develop liverdisease with various clinical outcomes ranging from an asymptomaticcarrier state to chronic active hepatitis and liver cirrhosis (occurringin about 20% of patients), which is strongly associated with thedevelopment of hepatocellular carcinoma (occurring in about 1-5% ofpatients). The World Health Organization estimates that 170 millionpeople are chronically infected with HCV, with an estimated 4 millionliving in the United States.

HCV has been implicated in cirrhosis of the liver and in induction ofhepatocellular carcinoma. The prognosis for patients suffering from HCVinfection remains poor as HCV infection is more difficult to treat thanother forms of hepatitis. Current data indicates a four-year survivalrate of below 50% for patients suffering from cirrhosis and a five-yearsurvival rate of below 30% for patients diagnosed with localizedresectable hepatocellular carcinoma. Patients diagnosed with localizedunresectable hepatocellular carcinoma fare even worse, having afive-year survival rate of less than 1%.

HCV is an enveloped RNA virus containing a single-strandedpositive-sense RNA genome approximately 9.5 kd in length. The RNA genomecontains a 5′-nontranslated region (5′ NTR) of 341 nucleotides, a largeopen reading frame (ORF) encoding a single polypeptide of 3,010 to 3,040amino acids, and a 3′-nontranslated region (3′-NTR) of variable lengthof about 230 nucleotides. HCV is similar in amino acid sequence andgenome organization to flaviviruses and pestiviruses, and therefore HCVhas been classified as a third genus of the family Flaviviridae.

The 5′ NTR, one of the most conserved regions of the viral genome,contains an internal ribosome entry site (IRES) which plays a pivotalrole in the initiation of translation of the viral polyprotein. A singlelong open reading frame encodes a polyprotein, which is co- orpost-translationally processed into structural (core, E1, E2 and p7) andnonstructural (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) viral proteins byeither cellular or viral proteinases. The 3′ NTR consists of threedistinct regions: a variable region of about 38 nucleotides followingthe stop codon of the polyprotein, a polyuridine tract of variablelength with interspersed substitutions of cytidines, and 98 nucleotides(nt) at the very 3′ end which are highly conserved among various HCVisolates. By analogy to other plus-strand RNA viruses, the 3′-NTR isthought to play an important role in viral RNA synthesis. The order ofthe genes within the genome is:NH₂—C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COOH.

Processing of the structural proteins core (C), envelope protein 1 and(E1, E2), and the p7 region is mediated by host signal peptidases. Incontrast, maturation of the nonstructural (NS) region is accomplished bytwo viral enzymes. The HCV polyprotein is first cleaved by a host signalpeptidase generating the structural proteins C/E1, E1/E2, E2/p7, andp7/NS2. The NS2-3 proteinase, which is a metalloprotease, then cleavesat the NS2/NS3 junction. The NS3/4A proteinase complex (NS3 being aserine protease and NS4A acting as a cofactor of the NS3 protease), isthen responsible for processing all the remaining cleavage junctions.RNA helicase and NTPase activities have also been identified in the NS3protein. One-third of the NS3 protein functions as a protease, and theremaining two-thirds of the molecule acts as the helicase/ATPase that isthought to be involved in HCV replication. NS5A may be phosphorylatedand acts as a putative cofactor of NS5B. The fourth viral enzyme, NS5B,is a membrane-associated RNA-dependent RNA polymerase (RdRp) and a keycomponent responsible for replication of the viral RNA genome. NS5Bcontains the “GDD” sequence motif, which is highly conserved among allRdRps characterized to date.

Replication of HCV is thought to occur in membrane-associatedreplication complexes. Within these, the genomic plus-strand RNA istranscribed into minus-strand RNA, which in turn can be used as atemplate for synthesis of progeny genomic plus-strands. At least twoviral enzymes appear to be involved in this reaction: the NS3helicase/NTPase, and the NS5B RNA-dependent RNA polymerase. While therole of NS3 in RNA replication is less clear, NS5B is the key enzymeresponsible for synthesis of progeny RNA strands. Using recombinantbaculoviruses to express NS5B in insect cells and a synthetic nonviralRNA as a substrate, two enzymatic activities have been identified asbeing associated with it: a primer-dependent RdRp and a terminaltransferase (TNTase) activity. It was subsequently confirmed and furthercharacterized through the use of the HCV RNA genome as a substrate.Other studies have shown that NS5B with a C-terminal 21 amino-acidtruncation expressed in Escherichia coli is also active for in vitro RNAsynthesis. On certain RNA templates, NS5B has been shown to catalyze RNAsynthesis via a de novo initiation mechanism, which has been postulatedto be the mode of viral replication in vivo. Templates withsingle-stranded 3′ termini, especially those containing a 3′-terminalcytidylate moiety, have been found to direct de novo synthesisefficiently. There has also been evidence for NS5B to utilize di- ortri-nucleotides as short primers to initiate replication.

It is well-established that persistent infection of HCV is related tochronic hepatitis, and as such, inhibition of HCV replication is aviable strategy for the prevention of hepatocellular carcinoma. Presenttreatment approaches for HCV infection suffer from poor efficacy andunfavorable side-effects and there is currently a strong effort directedto the discovery of HCV replication inhibitors that are useful for thetreatment and prevention of HCV related disorders. New approachescurrently under investigation include the development of prophylacticand therapeutic vaccines, the identification of interferons withimproved pharmacokinetic characteristics, and the discovery of agentsdesigned to inhibit the function of three major viral proteins:protease, helicase and polymerase. In addition, the HCV RNA genomeitself, particularly the IRES element, is being actively exploited as anantiviral target using antisense molecules and catalytic ribozymes.

Particular therapies for HCV infection include α-interferon monotherapyand combination therapy comprising α-interferon and ribavirin. Thesetherapies have been shown to be effective in some patients with chronicHCV infection. The use of antisense oligonucleotides for treatment ofHCV infection has also been proposed as has the use of free bile acids,such as ursodeoxycholic acid and chenodeoxycholic acid, and conjugatedbile acids, such as tauroursodeoxycholic acid. Phosphonoformic acidesters have also been proposed as potentially for the treatment ofvarious viral infections including HCV. Vaccine development, however,has been hampered by the high degree of viral strain heterogeneity andimmune evasion and the lack of protection against reinfection, even withthe same inoculum.

The development of small-molecule inhibitors directed against specificviral targets has become a major focus of anti-HCV research. Thedetermination of crystal structures for NS3 protease, NS3 RNA helicase,and NS5B polymerase has provided important structural insights thatshould assist in the rational design of specific inhibitors.

NS5B, the RNA-dependent RNA polymerase, is an important and attractivetarget for small-molecule inhibitors. Studies with pestiviruses haveshown that the small molecule compound VP32947(3-[((2-dipropylamino)ethyl)thio]-5H-1,2,4-triazino[5,6-b]indole) is apotent inhibitor of pestivirus replication and most likely inhibits theNS5B enzyme since resistant strains are mutated in this gene. Inhibitionof RdRp activity by (−)β-L-2′,3′-dideoxy-3′-thiacytidine 5′-triphosphate(3TC; lamivudine triphosphate) and phosphonoacetic acid also has beenobserved.

Despite the intensive effort directed at the treatment and prevention ofHCV and related viral infections, there exists a need in the art fornon-peptide, small-molecule compounds having desirable or improvedphysicochemical properties that are useful for inhibiting viruses andtreating viral infections and virus-related disorders.

SUMMARY OF THE INVENTION

The present invention provides certain ethenyl-substituted pyridine andpyrimidine derivatives (collectively referred to herein as “compounds ofthe invention”), compositions comprising such compounds, and methods fortheir use as HCV inhibitors and for treating viral infections anddisorders related thereto.

In one embodiment, the compounds of the invention have a generalstructure shown in Formula (A):

and include tautomers, isomers, and esters of said compounds, andpharmaceutically acceptable salts, solvates, and prodrugs of saidcompounds, tautomers, isomers, and esters, wherein each of R, R¹, X, Y,Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁸, R¹⁹, R²², R²³, and n areselected independently and wherein:R²² and R²³ are each independently selected from H, alkyl, andcycloalkyl;R is selected from H, alkyl, aryl, heteroaryl, cycloalkyl, aryl-fusedcycloalkyl, heteroaryl-fused cycloalkyl, cycloalkenyl, aryl-fusedcycloalkenyl, heteroaryl-fused cycloalkenyl, heterocycloalkyl,aryl-fused heterocycloalkyl, and heteroaryl-fused heterocycloalkyl,

-   -   wherein each of said alkyl, said aryl, said heteroaryl, said        cycloalkyl, said aryl-fused cycloalkyl, said heteroaryl-fused        cycloalkyl, said cycloalkenyl, said aryl-fused cycloalkenyl,        said heteroaryl-fused cycloalkenyl, said heterocycloalkyl, said        aryl-fused heterocycloalkyl, and said heteroaryl-fused        heterocycloalkyl, is unsubstituted or optionally independently        substituted with from one to three substituents, which are the        same or different, each substituent being independently selected        from halo, —OH, —CN, oxo, alkyl, cycloalkyl, alkenyl, alkynyl,        haloalkyl, heteroalkyl, heterohaloalkyl, -alkyl-OH, —O-alkyl,        —O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl,        —O-alkyl-aryl, —S-alkyl-aryl, heteroaryl, heteroarylalkyl-,        —O-heteroaryl, —S-heteroaryl, —O-alkyl-heteroaryl,        —S-alkyl-heteroaryl, heterocycloalkyl, heterocycloalkylalkyl-,        —C(O)-alkyl, —C(O)-haloalkyl, —C(O)-cycloalkyl,        —C(O)-heterocycloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl,        —C(O)O-haloalkyl, —C(O)O-cycloalkyl, —C(O)O-heterocycloalkyl,        —OC(O)-alkyl, —OC(O)-haloalkyl, —OC(O)-cycloalkyl,        —OC(O)-heterocycloalkyl, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹,        —OC(O)NH₂, —CO(O)NHR¹⁰, —CO(O)NR¹⁰R¹¹, —NH₂, —NHR¹⁰, —NR¹⁰R¹¹,        —NO₂, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰, —S(O)₂NH₂,        —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)₂R¹⁰, substituted aryl, and        substituted heteroaryl, wherein each of said substituted aryl        and said substituted heteroaryl independently contains from one        to five substituents, which may be the same or different, each        substituent being independently selected from halo, alkyl,        —O-alkyl, and —C(O)Oalkyl;        X and Y are each independently selected from N and CH, with the        proviso that at least one of X or Y is N;        Z═H, halo, —OH, —SH, —CN, alkyl, alkenyl, alkynyl, heteroalkyl,        haloalkyl, heterohaloalkyl, —S-alkyl, —O-alkyl, —O-aryl,        —O-heteroaryl, cycloalkyl, aryl, heteroaryl, —NH₂, —NHR¹², and        —NR¹²R¹³;        R¹ is selected from H, halo, alkyl, haloalkyl, heteroalkyl,        heterohaloalkyl, heteroaryl, —OH, —O-alkyl, —O-aryl,        —O-heteroalkyl, —O-heteroaryl, —SH, —S-alkyl, —S-aryl,        —S-heteroalkyl, —S-heteroaryl, —NH₂, —NHR¹⁴, —NR¹⁴R¹⁵, —NO₂,        —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹,        and —S(O)₂R¹⁰;        R² (when R² is not joined with R⁹) is selected from H and alkyl;        n=0, 1, or 2;        R³ is selected from H, -alkyl, -alkenyl, alkynyl, aryl,        heteroaryl, and cycloalkyl,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, and said cycloalkyl, is unsubstituted or        optionally independently substituted with from one to three        substituents, which can be the same or different, each        substituent being independently selected from halo, —OH, alkyl,        —O-alkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl,        —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl,        —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl,        —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;        R⁴ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl,        azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl,        —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰,        —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹,        —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl,        —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl,        heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;        R⁵ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl,        azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl,        —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰,        —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹,        —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl,        —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl,        heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;    -   or, alternatively, R⁴ and R⁵ are taken together with the carbon        atom to which they are shown attached to form a 3- to        7-membered, saturated or partially unsaturated, spirocycloalkyl        ring containing from 0 to 3 spiro ring heteroatoms selected from        O, N, and S:        R⁶ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl,        azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl,        —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰,        —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹,        —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl,        —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl,        heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;        or, alternatively, R⁵ and R⁶ are taken together to form a double        bond;        R⁷ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl,        azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl,        —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰,        —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹,        —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl,        —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl,        heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;    -   or, alternatively, R⁶ and R⁷ are taken together with the carbon        atom to which they are shown attached to form a 3- to        7-membered, saturated or partially unsaturated, spirocycloalkyl        ring containing from 0 to 3 spiro ring heteroatoms selected from        O, N, and S;        R⁸ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl,        azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl,        —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰,        —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹,        —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to five substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-cycloalkyl,        —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —O(C)O—N(R¹⁰)R¹,        —O(C)O—NHR¹¹, —O(C)O—NH₂, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, —S(O)₂R¹⁰,        —SR¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, —CN, —NH₂, —NHR¹⁶, and        —NR¹⁶R¹⁷, —N(R¹⁰)S(O)₂R¹⁰, —NHS(O)₂R¹⁰, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;        R⁹ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl,        azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl,        —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰,        —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹,        —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to five substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-cycloalkyl,        —O-alkenyl, haloalkyl, —O-haloalkenyl, —O(C)O—N(R¹⁰)R¹¹,        —O(C)O—NHR¹¹, —O(C)O—NH₂, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, —S(O)₂R¹⁰,        —SR¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, —CN, —NH₂, —NHR¹⁶, and        —NR¹⁶R¹⁷, —N(R¹⁰)S(O)₂R¹⁰, —NHS(O)₂R¹⁰, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;    -   or, alternatively, R⁸ and R⁹ are taken together with the carbon        atom to which they are shown attached to form a 3- to        7-membered, saturated or partially unsaturated, spirocycloalkyl        ring containing from 0 to 3 spiro ring heteroatoms selected from        O, N, and S;        each R¹⁸ (when present) is selected from H, —OH, halo, -alkyl,        -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl,        —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH₂, —NO₂,        —NHR¹⁰—NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰,        —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰, —S(O)₂NHR¹⁰,        —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl,        —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl,        heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;        each R¹⁹ (when present) is selected from H, —OH, halo, -alkyl,        -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl,        —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰,        —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰,        —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰, —S(O)₂NHR¹⁰,        —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl,        —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl,        heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;    -   or, alternatively, n is 1 and R¹⁸ and R¹⁹ are taken together        with the carbon atom to which they are attached to form a 3- to        7-membered, saturated or partially unsaturated, spirocycloalkyl        ring containing from 0 to 3 spiro ring heteroatoms selected from        O, N, and S;    -   or, alternatively, R⁴ and R⁷, together with the carbon atoms to        which they are shown attached, form a moiety (1C):

-   -   wherein R²⁰ and R²¹ are each independently selected from H,        alkyl, and heteroalkyl and wherein R⁵ and R⁶ are defined above,        with the proviso that when R⁴ and R⁷ form a moiety (1C), then R⁵        and R⁶ are not taken together to form a double bond;    -   or, alternatively, R⁴ and R⁷, together with the carbon atoms to        which they are shown attached, form a moiety (1D):

-   -   wherein R⁵ and R⁶ are as defined above;    -   or, alternatively, R⁴ and R⁷, together with the carbon atoms to        which they are shown attached, form a moiety (1E):

-   -   wherein R⁵ and R⁶ are as defined above;    -   each R¹⁰ is independently selected from alkyl, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl,        -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl,        —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl,        heterocycloalkenyl, aryl, and heteroaryl;    -   each R¹¹ is independently selected from alkyl, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl,        -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl,        —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl,        heterocycloalkenyl, aryl, and heteroaryl;    -   or, alternatively, R¹⁰ and R¹¹ are linked together with the        nitrogen to which they are attached to form an unsubstituted or        substituted 4- or 6-membered heterocycloalkyl;    -   each R¹² is independently selected from alkyl, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl,        -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl,        —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl,        heterocycloalkenyl, aryl, and heteroaryl;    -   each R¹³ is independently selected from alkyl, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl,        -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl,        —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl,        heterocycloalkenyl, aryl, and heteroaryl;    -   or, alternatively, R¹² and R¹³ are linked together with the        nitrogen to which they are attached to form an unsubstituted or        substituted 4- to 6-membered heterocycloalkyl;    -   each R¹⁴ is independently selected from alkyl, alkoxy, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, alkylamino, alkylthio,        heteroalkenyl, haloalkenyl, —S(O)₂-alkyl, -alkyl-OH,        alkyl-O-Acyl, —C(O)Oalkyl, —C(O)alkyl, cycloalkyl,        cycloalkyl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-,        heterocycloalkenyl, heterocycloalkenyl-alkyl-, aryl,        aryl-alkyl-, heteroaryl, and heteroaryl-alkyl-,    -   wherein each said alkyl, each said alkoxy, each said alkenyl,        each said haloalkyl, each said heteroalkyl, each said        heterohaloalkyl, each said alkylamino, each said alkylthio, each        said heteroalkenyl, each said haloalkenyl, each said        —S(O)₂-alkyl, each said -alkyl-OH, each said -alkyl-O-Acyl, each        said —C(O)Oalkyl, each said —C(O)alkyl, each said cycloalkyl,        each said cycloalkyl-alkyl-, each said heterocycloalkyl, each        said heterocycloalkyl-alkyl-, each said heterocycloalkenyl, each        said heterocycloalkenyl-alkyl-, each said aryl, each said        aryl-alkyl-, each said heteroaryl, and each said        heteroaryl-alkyl-, is unsubstituted or optionally independently        substituted with from one to three substituent, which can be the        same or different, each substitutent being independently        selected from —OH, halo, —NH₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH,        —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)₂alkyl,        —S(O)₂aryl, alkyl, alkoxy, haloalkyl, haloalkoxy, heteroalkyl,        heteroalkyl, heterohaloalkyl, aryl, cycloalkyl, and        heterocycloalkyl;    -   each R¹⁵ is independently selected from alkyl, alkoxy, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, alkylamino, alkylthio,        heteroalkenyl, haloalkenyl, —S(O)₂-alkyl, -alkyl-OH,        -alkyl-O-Acyl, —C(O)Oalkyl, —C(O)alkyl, cycloalkyl,        cycloalkyl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-,        heterocycloalkenyl, heterocycloalkenyl-alkyl-, aryl,        aryl-alkyl-, heteroaryl, and heteroaryl-alkyl-,    -   wherein each said alkyl, each said alkoxy, each said alkenyl,        each said haloalkyl, each said heteroalkyl, each said        heterohaloalkyl, each said alkylamino, each said alkylthio, each        said heteroalkenyl, each said haloalkenyl, each said        —S(O)₂-alkyl, each said -alkyl-OH, each said -alkyl-O-Acyl, each        said —C(O)Oalkyl, each said —C(O)alkyl, each said cycloalkyl,        each said cycloalkyl-alkyl-, each said heterocycloalkyl, each        said heterocycloalkyl-alkyl-, each said heterocycloalkenyl, each        said heterocycloalkenyl-alkyl-, each said aryl, each said        aryl-alkyl-, each said heteroaryl, and each said        heteroaryl-alkyl-, is unsubstituted or optionally independently        substituted with from one to three substituent, which can be the        same or different, each substitutent being independently        selected from —OH, halo, —NH₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH,        —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, S(O)₂alkyl,        —S(O)₂aryl, alkyl, alkoxy, haloalkyl, haloalkoxy, heteroalkyl,        heteroalkyl, heterohaloalkyl, aryl, cycloalkyl, and        heterocycloalkyl;    -   or, alternatively, R¹⁴ and R¹⁵ are linked together with the        nitrogen to which they are attached to form an unsubstituted or        substituted 4- to 6-membered heterocycloalkyl;    -   each R¹⁶ is independently selected from alkyl, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl,        -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl,        —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl,        heterocycloalkenyl, aryl, and heteroaryl; and    -   each R¹⁷ is independently selected from alkyl, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl,        -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl,        —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl,        heterocycloalkenyl, aryl, and heteroaryl;    -   or, alternatively, R¹⁶ and R¹⁷ are linked together with the        nitrogen to which they are attached to form an unsubstituted or        substituted 4- or 6-membered heterocycloalkyl.

In another embodiment, the invention provides compositions, includingpharmaceutical compositions, comprising one or more compounds of theinvention (e.g., one compound of the invention), or a pharmaceuticallyacceptable salt, solvate, ester, or prodrug thereof, and apharmaceutically acceptable carrier or diluent. In one embodiment, saidcompound or compounds of the invention are present in the composition inan amount effective for inhibiting HCV, and/or for treating orpreventing a viral infection or a virus-related disorder in a patient inneed thereof.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising one or more compounds of the invention, or apharmaceutically acceptable salt, solvate, ester, or prodrug thereof,together with one or more additional therapeutic agents, optionallyfurther comprising a pharmaceutically effective carrier or diluent.Non-limiting examples of such additional therapeutic agents include oneor more of any of the following: HCV polymerase inhibitors, HCV proteaseinhibitors, HCV replicase inhibitors, nucleosides, Interferon, and/orribavirin (or Levovirin or Viramidine). Non-limiting examples ofinterferon include PEG-interferon, PEG interferon alpha conjugate,alpha-interferon, and pegylated interferon. These and other examples areknown to those of ordinary skill in the art.

In another embodiment, the present invention provides for the use of oneor more compounds of the invention, or a pharmaceutically acceptablesalt, solvate, ester, and/or prodrug thereof, alone or in combinationwith one or more additional therapeutic agents such as those describedabove, for inhibiting HCV and/or for treating or preventing a viralinfection or a virus-related disorder in a patient in need thereof.

In another embodiment, the invention provides a method of inhibiting HCVin vivo, ex vivo, or in vitro, comprising exposing a population of cellscomprising HCV to an effective amount of at least one compound of theinvention, or a pharmaceutically acceptable salt, solvate, ester, orprodrug thereof, alone or in combination with one or more additionaltherapeutic agents such as those described above. In one suchembodiment, the compound or compounds of the invention are used as theneat chemical. In another such embodiment, the compounds of theinvention are used in the form of a pharmaceutically acceptablecomposition.

In another embodiment, the invention provides a method for treating orpreventing a viral infection or a virus-related disorder in a patient,comprising administering to the patient an effective amount of at leastone compound of the invention, or a pharmaceutically acceptable salt,solvate, ester, or prodrug thereof, alone or in combination with one ormore additional therapeutic agents such as those described above. In onesuch embodiment, the compound or compounds of the invention are used asthe neat chemical. In another such embodiment, the compounds of theinvention are used in the form of a pharmaceutically acceptablecomposition.

The details of the invention are set forth in the accompanying detaileddescription below. Although any methods and materials similar to thosedescribed herein can be used in the practice or testing of the presentinvention, illustrative methods and materials are described herein.Other features, objects, and advantages of the invention will beapparent from the description and the claims. All patents andpublications cited in this specification are incorporated herein byreference.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the compounds of the invention have the structuralFormula (A) as described above, and include pharmaceutically acceptablesalts, esters, prodrugs, tautomers, and isomers of said compounds.

In one embodiment, in Formula (A), R²² and R²³ are each independentlyselected from H and alkyl.

In one embodiment, in Formula (A), R²² and R²³ are each H and thecompounds of the invention have a general structure shown in Formula(I):

and include tautomers, isomers, and esters of said compounds, andpharmaceutically acceptable salts, solvates, and prodrugs of saidcompounds, tautomers, isomers, and esters, wherein each of R, R¹, X, Y,Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁸, R¹⁹ and n are selectedindependently and wherein:R is selected from H, alkyl, aryl, heteroaryl, cycloalkyl, aryl-fusedcycloalkyl, heteroaryl-fused cycloalkyl, cycloalkenyl, aryl-fusedcycloalkenyl, heteroaryl-fused cycloalkenyl, heterocycloalkyl,aryl-fused heterocycloalkyl, and heteroaryl-fused heterocycloalkyl,

-   -   wherein each of said alkyl, said aryl, said heteroaryl, said        cycloalkyl, said aryl-fused cycloalkyl, said heteroaryl-fused        cycloalkyl, said cycloalkenyl, said aryl-fused cycloalkenyl,        said heteroaryl-fused cycloalkenyl, said heterocycloalkyl, said        aryl-fused heterocycloalkyl, and said heteroaryl-fused        heterocycloalkyl, is unsubstituted or optionally independently        substituted with from one to five substituents, which are the        same or different, each substituent being independently selected        from halo, —OH, —CN, oxo, alkyl, cycloalkyl, alkenyl, alkynyl,        haloalkyl, heteroalkyl, heterohaloalkyl, -alkyl-OH, —O-alkyl,        —O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl,        —O-alkyl-aryl, —S-alkyl-aryl, heteroaryl, heteroarylalkyl-,        —O-heteroaryl, —S-heteroaryl, —O-alkyl-heteroaryl,        —S-alkyl-heteroaryl, heterocycloalkyl, heterocycloalkylalkyl-,        —C(O)-alkyl, —C(O)-haloalkyl, —C(O)-cycloalkyl,        —C(O)-heterocycloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl,        —C(O)O-haloalkyl, —C(O)O-cycloalkyl, —C(O)O-heterocycloalkyl,        —OC(O)-alkyl, —OC(O)-haloalkyl, —OC(O)-cycloalkyl,        —OC(O)-heterocycloalkyl, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹,        —OC(O)NH₂, —CO(O)NHR¹⁰, —CO(O)NR¹⁰R¹¹, —NH₂, —NHR¹⁰, —NR¹⁰R¹¹,        —NO₂, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰, —S(O)₂NH₂,        —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)₂R¹⁰, substituted aryl, and        substituted heteroaryl, wherein each of said substituted aryl        and said substituted heteroaryl independently contains from one        to three substituents, which may be the same or different, each        substituent being independently selected from halo, alkyl,        —O-alkyl, and —C(O)Oalkyl;        X and Y are each independently selected from N and CH, with the        proviso that at least one of X or Y is N;        Z═H, halo, —OH, —SH, —CN, alkyl, alkenyl, alkynyl, heteroalkyl,        haloalkyl, heterohaloalkyl, —S-alkyl, —O-alkyl, —O-aryl,        —O-heteroaryl, cycloalkyl, aryl, heteroaryl, —NH₂, —NHR¹², and        —NR¹²R¹³;        R¹ is selected from H, halo, alkyl, haloalkyl, heteroalkyl,        heterohaloalkyl, heteroaryl, —OH, —O-alkyl, —O-aryl,        —O-heteroalkyl, —O-heteroaryl, —SH, —S-alkyl, —S-aryl,        —S-heteroalkyl, —S-heteroaryl, —NH₂, —NHR¹⁴, —NR¹⁴R¹⁵, —NO₂,        —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹; —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹,        and —S(O)₂R¹⁰;        R² (when R² is not joined with R⁹) is selected from H and alkyl;        n=0, 1, or 2;        R³ is selected from H, -alkyl, -alkenyl, alkynyl, aryl,        heteroaryl, and cycloalkyl,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, and said cycloalkyl, is unsubstituted or        optionally independently substituted with from one to three        substituents, which can be the same or different, each        substituent being independently selected from halo, —OH, alkyl,        —O-alkyl, —O-alkenyl, —O-haloalkyl, haloalkenyl, —OC(O)-alkyl,        —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl,        —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl,        —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl,        heterocycloalkyl, and heterocycloalkenyl;        R⁴ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl,        azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl,        —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰,        —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹,        —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl,        —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl,        heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;        R⁵ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl,        azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl,        —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰,        —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹,        —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl,        —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl,        heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;    -   or, alternatively, R⁴ and R⁵ are taken together with the carbon        atom to which they are shown attached to form a 3- to        7-membered, saturated or partially unsaturated, spirocycloalkyl        ring containing from 0 to 3 Spiro ring heteroatoms selected from        O, N, and S;        R⁶ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl,        azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl,        —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰,        —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹,        —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl,        —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl,        heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;    -   or, alternatively, R⁵ and R⁶ are taken together to form a double        bond;        R⁷ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl,        azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl,        —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰,        —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹,        —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl,        —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl,        heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;    -   or, alternatively, R⁶ and R⁷ are taken together with the carbon        atom to which they are shown attached to form a 3- to        7-membered, saturated or partially unsaturated, spirocycloalkyl        ring containing from 0 to 3 spiro ring heteroatoms selected from        O, N, and S;        R⁸ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl,        azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl,        —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —C(O)OH, —C(O)OR¹⁰, —C(O)NH₂,        —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰,        —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to five substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-cycloalkyl,        —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —O(C)O—N(R¹⁰)R¹¹,        —O(C)O—NHR¹¹, —O(C)O—NH₂, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, —S(O)₂R¹⁰,        —SR¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, —CN, —NH₂, —NHR¹⁶, and        —NR¹⁶R¹⁷, —N(R¹⁰)S(O)₂R¹⁰, —NHS(O)₂R¹⁰, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;        R⁹ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl,        azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl,        —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —C(O)OH, —C(O)OR¹⁰, —C(O)NH₂,        —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰,        —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to five substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-cycloalkyl,        —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —O(C)O—N(R¹⁰)R¹¹,        —O(C)O—NHR¹¹, —O(C)O—NH₂, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, —S(O)₂R¹⁰,        —SR¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, —CN, —NH₂, —NHR¹⁶, and        —NR¹⁶R¹⁷, —N(R¹⁰)S(O)₂R¹⁰, —NHS(O)₂R¹⁰, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;    -   or, alternatively, R⁸ and R⁹ are taken together with the carbon        atom to which they are shown attached to form a 3- to        7-membered, saturated or partially unsaturated, spirocycloalkyl        ring containing from 0 to 3 spiro ring heteroatoms selected from        O, N, and S;        each R¹⁸ (when present) is selected from H, —OH, halo, -alkyl,        -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl,        —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰,        —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰,        —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰, —S(O)₂NHR¹⁰,        —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl,        —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl,        heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;        each R¹⁹ (when present) is selected from H, —OH, halo, -alkyl,        -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl,        —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰,        —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰,        —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰, —S(O)₂NHR¹⁰,        —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl,        —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl,        heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;    -   or, alternatively, n is 1 and R¹⁸ and R¹⁹ are taken together        with the carbon atom to which they are attached to form a 3- to        7-membered, saturated or partially unsaturated, spirocycloalkyl        ring containing from 0 to 3 spiro ring heteroatoms selected from        O, N, and S;    -   or, alternatively, R⁴ and R⁷, together with the carbon atoms to        which they are shown attached, form a moiety (1C):

-   -   wherein R²⁰ and R²¹ are each independently selected from H,        alkyl, and heteroalkyl and wherein R⁵ and R⁶ are defined above,        with the proviso that when R⁴ and R⁷ form a moiety (1C), then R⁵        and R⁶ are not taken together to form a double bond;    -   or, alternatively, R⁴ and R⁷, together with the carbon atoms to        which they are shown attached, form a moiety (1D):

-   -   wherein R⁵ and R⁶ are as defined above;    -   or, alternatively, R⁴ and R⁷, together with the carbon atoms to        which they are shown attached, form a moiety (1E):

-   -   wherein R⁵ and R⁶ are as defined above;    -   each R¹⁰ is independently selected from alkyl, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl,        -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl,        —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl,        heterocycloalkenyl, aryl, and heteroaryl;    -   each R¹¹ is independently selected from alkyl, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl,        -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl,        —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl,        heterocycloalkenyl, aryl, and heteroaryl;    -   or, alternatively, R¹⁰ and R¹¹ are linked together with the        nitrogen to which they are attached to form an unsubstituted or        substituted 4- or 6-membered heterocycloalkyl;    -   each R¹² is independently selected from alkyl, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl,        -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl,        —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl,        heterocycloalkenyl, aryl, and heteroaryl;    -   each R¹³ is independently selected from alkyl, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl,        -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl,        —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl,        heterocycloalkenyl, aryl, and heteroaryl;    -   or, alternatively, R¹² and R¹³ are linked together with the        nitrogen to which they are attached to form an unsubstituted or        substituted 4- to 6-membered heterocycloalkyl;    -   each R¹⁴ is independently selected from alkyl, alkoxy, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, alkylamino, alkylthio,        heteroalkenyl, haloalkenyl, —S(O)₇-alkyl, -alkyl-OH,        alkyl-O-Acyl, —C(O)Oalkyl, —C(O)alkyl, cycloalkyl,        cycloalkyl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-,        heterocycloalkenyl, heterocycloalkenyl-alkyl-, aryl,        aryl-alkyl-, heteroaryl, and heteroaryl-alkyl-,    -   wherein each said alkyl, each said alkoxy, each said alkenyl,        each said haloalkyl, each said heteroalkyl, each said        heterohaloalkyl, each said alkylamino, each said alkylthio, each        said heteroalkenyl, each said haloalkenyl, each said        —S(O)₂-alkyl, each said -alkyl-OH, each said -alkyl-O-Acyl, each        said —C(O)Oalkyl, each said —C(O)alkyl, each said cycloalkyl,        each said cycloalkyl-alkyl-, each said heterocycloalkyl, each        said heterocycloalkyl-alkyl-, each said heterocycloalkenyl, each        said heterocycloalkenyl-alkyl-, each said aryl, each said        aryl-alkyl-, each said heteroaryl, and each said        heteroaryl-alkyl-, is unsubstituted or optionally independently        substituted with from one to three substituent, which can be the        same or different, each substitutent being independently        selected from —OH, halo, —NH₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH,        —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)₂alkyl,        —S(O)₂aryl, alkyl, alkoxy, haloalkyl, haloalkoxy, heteroalkyl,        heteroalkyl, heterohaloalkyl, aryl, cycloalkyl, and        heterocycloalkyl;    -   each R¹⁵ is independently selected from alkyl, alkoxy, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, alkylamino, alkylthio,        heteroalkenyl, haloalkenyl, —S(O)₂-alkyl, -alkyl-OH,        -alkyl-O-Acyl, —C(O)Oalkyl, —C(O)alkyl, cycloalkyl,        cycloalkyl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-,        heterocycloalkenyl, heterocycloalkenyl-alkyl-, aryl,        aryl-alkyl-, heteroaryl, and heteroaryl-alkyl-,    -   wherein each said alkyl, each said alkoxy, each said alkenyl,        each said haloalkyl, each said heteroalkyl, each said        heterohaloalkyl, each said alkylamino, each said alkylthio, each        said heteroalkenyl, each said haloalkenyl, each said        —S(O)₂-alkyl, each said -alkyl-OH, each said -alkyl-O-Acyl, each        said —C(O)Oalkyl, each said —C(O)alkyl, each said cycloalkyl,        each said cycloalkyl-alkyl-, each said heterocycloalkyl, each        said heterocycloalkyl-alkyl-, each said heterocycloalkenyl, each        said heterocycloalkenyl-alkyl-, each said aryl, each said        aryl-alkyl-, each said heteroaryl, and each said        heteroaryl-alkyl-, is unsubstituted or optionally independently        substituted with from one to three substituent, which can be the        same or different, each substitutent being independently        selected from —OH, halo, —NH₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH,        —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)₂alkyl,        —S(O)₂aryl, alkyl, alkoxy, haloalkyl, haloalkoxy, heteroalkyl,        heteroalkyl, heterohaloalkyl, aryl, cycloalkyl, and        heterocycloalkyl;    -   or, alternatively, R¹⁴ and R¹⁵ are linked together with the        nitrogen to which they are attached to form an unsubstituted or        substituted 4- to 6-membered heterocycloalkyl;    -   each R¹⁶ is independently selected from alkyl, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl,        -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, cycloalkyl,        heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; and    -   each R¹⁷ is independently selected from alkyl, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl,        -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, cycloalkyl,        heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl;    -   or, alternatively, R¹⁶ and R¹⁷ are linked together with the        nitrogen to which they are attached to form an unsubstituted or        substituted 4- or 6-membered heterocycloalkyl.

In one embodiment, in Formula (I), each of R³, R⁵, R⁶, and R⁸ is H.

In one embodiment, in Formula (I), n is 1; each of R², R³, R⁵, R⁶, R⁸,R¹⁸ and R¹⁹ is H; R⁴ and R⁷ are OH; and R⁹ is alkyl, wherein said alkylis unsubstituted or substituted with from one to five substituents,which can be the same or different, each substituent being independentlyselected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl,—O-alkyl, —O-cycloalkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl,—OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl,—O(C)O—NHR¹⁰, —O(C)O—N(R¹⁰)R¹¹, —C(O)O-alkyl, —C(O)O-alkenyl,—C(O)O-haloalkyl, —C(O)O-haloalkenyl, —S(O)₂R¹⁰, —SR¹⁰, —S(O)₂NHR¹⁰,—S(O)₂NR¹⁰R¹¹, —CN, —NH₂, —NHR¹⁶, and —NR¹⁶R¹⁷, —NHS(O)₂R¹⁰,—N(R¹⁰)S(O)₂R¹⁰, aryl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, and heterocycloalkenyl.

In one embodiment, in Formula (I), n is 1; each of R², R³, R⁵, R⁶, R⁸,R¹⁸ and R¹⁹ is H; R⁴ and R⁷ are OH; and R⁹ is alkyl, wherein said alkylis unsubstituted or substituted with from one to five groupsindependently selected from —OH, halo, —CN, —NH₂, —NHR¹⁶, —NR¹⁶R¹⁷,—NHS(O)₂R¹⁰, —N(R¹⁰)S(O)₂R¹⁰, -Oalkyl, -Ocycloalkyl,—O-alkyl-cycloalkyl, —OC(O)-alkyl, —O(C)O—NHR¹⁰, —O(C)O—N(R¹⁰)R¹¹,—C(O)O-alkyl, —S(O)₂R¹⁰, —SR¹⁰, —S(O)₂NHR¹⁰, and —S(O)₂NR¹⁰R¹¹.

In one embodiment, in Formula (I), n is 1; each R², R³, R⁵, R⁶, R⁸, R¹⁸and R¹⁹ is H; R⁴ and R⁷ are OH; and R⁹ is methyl, wherein said methyl isunsubstituted or substituted with from one to three groups independentlyselected from —OH, halo, alkyl, —CN, —NH₂, —NHR¹⁶, —NR¹⁶R¹⁷,—NHS(O)₂R¹⁰, —N(R¹⁰)S(O)₂R¹⁰, -Oalkyl, -Ocycloalkyl,—O-alkyl-cycloalkyl, —OC(O)-alkyl, —O(C)O—NHR¹⁰, —O(C)O—N(R¹⁰)R¹¹,—C(O)O-alkyl, —S(O)₂R¹⁰—SR¹⁰, —S(O)₂NHR¹⁰, and —S(O)₂NR¹⁰R¹¹.

In some embodiments, R⁹ is -alkyl-NHS(O)₂R¹⁰, wherein R¹⁰ is selectedfrom methyl, ethyl, and cyclopropyl.

In some embodiments, R⁹ is selected from -alkyl —N(CH₃)S(O)₂R¹⁰ and-alkyl-N(CH₂CH₃)S(O)₂R¹⁰, wherein R¹⁰ is selected from methyl, ethyl,and cyclopropyl.

In some embodiments, R⁹ is -alkyl-O(C)O—NHR¹⁰, wherein R¹⁰ is selectedfrom methyl, ethyl, and cyclopropyl.

In some embodiments, R⁹ is selected from R⁹-alkyl-O(C)O—N(CH₃)R¹⁰ and—O(C)O—N(CH₂CH₃)R¹⁰, wherein R¹⁰ is selected from methyl, ethyl, andcyclopropyl.

In one embodiment, in Formula (I), n is 1; each of R², R³, R⁵, R⁶, R⁸,R¹⁸ and leis H; R⁴ and R⁷ are OH; and R⁹ is selected from —CH₂—O-alkyl,—CH₂—OH, —CH₃, H, —CH₂—CH₃, —CH₂—OC(O)CF₃, —CH₂—NH₂, —CH₂—NHR¹⁶, and—CH₂—NR¹⁶R¹⁷.

In one embodiment, in Formula (I), each of R³, R⁵, R⁶, and R⁸ is H andeach of R⁴ and R⁷ is —OH.

In one embodiment, in Formula (I), each of R³, R⁵, R⁶, and R⁸ is H; eachof R⁴ and R⁷ is —OH; and R⁹ is —O-alkyl.

In one embodiment, in Formula (I), each of R³, R⁵, R⁶, and R⁸ is H; eachof R⁴ and R⁷ is —OH; and R⁹ is —O—CH₃.

In one embodiment, in Formula (I), each of R³, R⁵, R⁶, and R⁸ is H; eachof R⁴ and R⁷ is —OH; R⁹ is —O—CH₃, and n is 1.

In one embodiment, in Formula (I), each of R³, R⁵, R⁶, and R⁸ is H; eachof R⁴ and R⁷ is —OH; R⁹ is —O—CH₃, and n is 2.

In one embodiment, the compounds of the invention have the structuralFormula (I.A):

and includes tautomers, isomers, and esters of such compounds, andpharmaceutically acceptable salts, solvates, and prodrugs of saidcompounds, tautomers, isomers, and esters, wherein each of R, R¹, X, Y,Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁸, R¹⁹ and n are selectedindependently and wherein:R, R¹, R², X, Y, Z, and n are as defined in Formula (I);R³ is selected from H, -alkyl, -alkenyl, alkynyl, aryl, heteroaryl, andcycloalkyl,

-   -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, and said cycloalkyl, is unsubstituted or        optionally independently substituted with from one to three        substituents, which can be the same or different, each        substituent being independently selected from halo, —OH, alkyl,        —O-alkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl,        —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl,        —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl,        —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;        R⁴ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl,        azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl,        —SH, —S-alkyl, —NH₂, —NHalkyl, and —N(alkyl)₂,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl, is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, —O-alkyl,        —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl,        —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl,        —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl,        —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl,        heterocycloalkyl, and heterocycloalkenyl;        R⁵ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl,        azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl,        —SH, —S-alkyl, —NH₂, —NHalkyl, and —N(alkyl)₂,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl, is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, —O-alkyl,        —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl,        —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl,        —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl,        —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl,        heterocycloalkyl, and heterocycloalkenyl,        R⁶ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl,        azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl,        —SH, —S-alkyl, —NH₂, —NHalkyl, and —N(alkyl)₂,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl, is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, —O-alkyl,        —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl,        —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl,        —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl,        —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl,        heterocycloalkyl, and heterocycloalkenyl;        R⁷ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl,        azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl,        —SH, —S-alkyl, —NH₂, —NHalkyl, and —N(alkyl)₂,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl, is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, —O-alkyl,        —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl,        —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl,        —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl,        —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl,        heterocycloalkyl, and heterocycloalkenyl;    -   or, alternatively, R⁶ and R⁷ are taken together with the carbon        atom to which they are shown attached to form a 3- to        7-membered, saturated or partially unsaturated, spirocycloalkyl        ring containing from 0 to 3 spiro ring heteroatoms selected from        O, N, and S;        R⁸ is selected from is selected from H, —OH, halo, -alkyl,        -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl,        —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH₂, —NHalkyl, and        —N(alkyl)₂,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to five substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-cycloalkyl,        —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —O(C)O—N(R¹⁰)R¹¹,        —O(C)O—NHR¹—O(C)O—NH₂, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, —S(O)₂R¹⁰,        —SR¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, —CN, —NH₂, —NHR¹⁶, and        —NR¹⁶R¹⁷, —N(R¹⁰)S(O)₂R¹⁰, —NHS(O)₂R¹⁰, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;        R⁹ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl,        azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl,        —SH, —S-alkyl, —NH₂, —NHalkyl, and —N(alkyl)₂,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to five substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-cycloalkyl,        —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —O(C)O—N(R¹⁰)R¹¹,        —O(C)O—NHR¹, —O(C)O—NH₂, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, —S(O)₂R¹⁰,        —SR¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, —CN, —NH₂, —NHR¹⁶, and        —NR¹⁶R¹⁷, —N(R¹⁰)S(O)₂R¹⁰, —NHS(O)₂R¹⁰, aryl, heteroaryl,        cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl;        each R¹⁸ (when present) is independently selected from H, —OH,        halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl,        —O-alkyl, —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH₂,        —NHalkyl, and —N(alkyl)₂,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl, is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, —O-alkyl,        —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl,        —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl,        —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl,        —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl,        heterocycloalkyl, and heterocycloalkenyl;        each R¹⁹ (when present) is independently selected from H, —OH,        halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl,        —O-alkyl, —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH₂,        —NHalkyl, and —N(alkyl)₂,    -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl, is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, —O-alkyl,        —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl,        —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl,        —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl,        —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl,        heterocycloalkyl, and heterocycloalkenyl;    -   each R¹⁰ is independently selected from alkyl, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl,        -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl,        —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl,        heterocycloalkenyl, aryl, and heteroaryl;    -   each R¹¹ is independently selected from alkyl, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl,        -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl,        —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl,        heterocycloalkenyl, aryl, and heteroaryl;    -   or, alternatively, R¹⁰ and R¹¹ are linked together with the        nitrogen to which they are attached to form an unsubstituted or        substituted 4- or 6-membered heterocycloalkyl;    -   each R¹² is independently selected from alkyl, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl,        -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl,        —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl,        heterocycloalkenyl, aryl, and heteroaryl;    -   each R¹³ is independently selected from alkyl, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl,        -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl,        —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl,        heterocycloalkenyl, aryl, and heteroaryl;    -   or, alternatively, R¹² and R¹³ are linked together with the        nitrogen to which they are attached to form an unsubstituted or        substituted 4- to 6-membered heterocycloalkyl;    -   each R¹⁴ is independently selected from alkyl, alkoxy, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, alkylamino,        heteroalkenyl, haloalkenyl, —S(O)₂-alkyl, -alkyl-OH,        -alkyl-O-Acyl, —C(O)Oalkyl, —C(O)alkyl, cycloalkyl,        cycloalkyl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-,        heterocycloalkenyl, heterocycloalkenyl-alkyl-, aryl,        aryl-alkyl-, heteroaryl, and heteroaryl-alkyl-,    -   wherein each said alkyl, each said alkoxy, each said alkenyl,        each said haloalkyl, each said heteroalkyl, each said        heterohaloalkyl, each said alkylamino, each said heteroalkenyl,        each said haloalkenyl, each said —S(O)₂-alkyl, each said        -alkyl-OH, each said -alkyl-O-Acyl, each said —C(O)Oalkyl, each        said —C(O)alkyl, each said cycloalkyl, each said        cycloalkyl-alkyl-, each said heterocycloalkyl, each said        heterocycloalkyl-alkyl-, each said heterocycloalkenyl, each said        heterocycloalkenyl-alkyl-, each said aryl, each said        aryl-alkyl-, each said heteroaryl, and each said        heteroaryl-alkyl-, is unsubstituted or optionally independently        substituted with from one to three substituent, which can be the        same or different, each substitutent being independently        selected from halo, —OH, —NH₂, —NHalkyl, —N(alkyl)₂, alkyl,        alkoxy, haloalkyl, haloalkoxy, heteroalkyl, heteroalkyl, and        heterohaloalkyl;    -   each R¹⁵ is independently selected from alkyl, alkoxy, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, alkylamino,        heteroalkenyl, haloalkenyl, —S(O)₂-alkyl, -alkyl-OH,        -alkyl-O-Acyl, —C(O)Oalkyl, —C(O)alkyl, cycloalkyl,        cycloalkyl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-,        heterocycloalkenyl, heterocycloalkenyl-alkyl-, aryl,        aryl-alkyl-, heteroaryl, and heteroaryl-alkyl-,    -   wherein each said alkyl, each said alkoxy, each said alkenyl,        each said haloalkyl, each said heteroalkyl, each said        heterohaloalkyl, each said alkylamino, each said heteroalkenyl,        each said haloalkenyl, each said —S(O)₂-alkyl, each said        -alkyl-OH, each said -alkyl-O-Acyl, each said —C(O)Oalkyl, each        said —C(O)alkyl, each said cycloalkyl, each said        cycloalkyl-alkyl-, each said heterocycloalkyl, each said        heterocycloalkyl-alkyl-, each said heterocycloalkenyl, each said        heterocycloalkenyl-alkyl-, each said aryl, each said        aryl-alkyl-, each said heteroaryl, and each said        heteroaryl-alkyl-, is unsubstituted or optionally independently        substituted with from one to three substituent, which can be the        same or different, each substitutent being independently        selected from halo, —OH, —NH₂, —NHalkyl, —N(alkyl)₂, alkyl,        alkoxy, haloalkyl, haloalkoxy, heteroalkyl, heteroalkyl, and        heterohaloalkyl;    -   or, alternatively, R¹⁴ and R¹⁵ are linked together with the        nitrogen to which they are attached to form an unsubstituted or        substituted 4- to 6-membered heterocycloalkyl;    -   each R¹⁶ is independently selected from alkyl, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl,        -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, cycloalkyl,        heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; and    -   each R¹⁷ is independently selected from alkyl, alkenyl,        haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl,        -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, cycloalkyl,        heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl;    -   or, alternatively, R¹⁶ and R¹⁷ are linked together with the        nitrogen to which they are attached to form an unsubstituted or        substituted 4- or 6-membered heterocycloalkyl.

As stated herein, the invention includes tautomers, rotamers,diastereomers, enantiomers and other stereoisomers of the compounds ofthe invention also. Thus, as one skilled in the art appreciates, in thecompounds of Formula (I) above, and the compounds of Formulas (I.A),(I.a), (I.a.1), (I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i),(I.a.4), (I.a.4.i), (I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7),(I.a.7.i), (I.a.8), (I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B),(I.b), (I.b.1), (I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1),(I.c.1.i), (I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E),(II), (II.A), and (II.A.1), and the compounds of Table I, below, themoiety

represents all isomeric forms (e.g., cis, trans, E, and S typerelationships and mixtures thereof). All such variations arecontemplated to be within the scope of the invention.

In one embodiment, the compounds of the invention have the structuralFormula (I.a):

and includes pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², R⁴, R⁵,R⁷, and R⁹ is selected independently and defined in Formula (I).

In one embodiment, in Formula (I.a), n is 1; R² is H; R⁴ and R⁷ are eachindependently selected from H and OH; R⁵ is selected from H, halo, andalkyl; and R⁹ is selected from H, —COOH, —C(O)O-alkyl, —OC(O)-alkyl,—C(O)O-aryl, —OC(O)-aryl, —C(O)O-alkyl-aryl, —OC(O)-alkyl-aryl,—C(O)O-alkyl-heteroaryl, —OC(O)-alkyl-heteroaryl, alkyl, —O-alkyl,heteroalkyl, haloalkyl, heterohaloalkyl, —O-heteroalkyl, —O-haloalkyl,—O-heterohaloalkyl, -alkyl-OH, -alkyl-OC(O)-alkyl,-alkyl-OC(O)-haloalkyl, -alkyl-NH₂, -alkyl-NHR¹⁶, and -alkyl-NR¹⁶R¹⁷.

In one embodiment, in Formula (I.a), n is 1; each of R², R³, R⁵, R⁶, R⁸,R¹⁸ and R¹⁹ is H; R⁴ and R⁷ are OH; and R⁹ is alkyl, wherein said alkylis unsubstituted or substituted with from one to five substituents,which can be the same or different, each substituent being independentlyselected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl,alkyl, —O-cycloalkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl,—OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl,—O(C)O—NHR¹⁰, —O(C)O—N(R¹⁰)R¹¹, —C(O)O-alkyl, —C(O)O-alkenyl,—C(O)O-haloalkyl, —C(O)O-haloalkenyl, —S(O)₂R¹⁰, —SR¹⁰, —S(O)₂NHR¹⁰,—S(O)₂NR¹⁰R¹¹, —CN, —NH₂, —NHR¹⁶, and —NR¹⁶R¹⁷, —NHS(O)₂R¹⁰,—N(R¹⁰)S(O)₂R¹⁰, aryl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, and heterocycloalkenyl.

In one embodiment, in Formula (I.a), n is 1; each of R², R³, R⁵, R⁶, R⁸,R¹⁸ and R¹⁹ is H; R⁴ and R⁷ are OH; and R⁹ is alkyl, wherein said alkylis unsubstituted or substituted with from one to five groupsindependently selected from —OH, halo, —CN, —NH₂, —NHR¹⁶, —NR¹⁶R¹⁷,—NHS(O)₂R¹⁰, —N(R¹⁰)S(O)₂R¹⁰, -Oalkyl, -Ocycloalkyl,—O-alkyl-cycloalkyl, —OC(O)-alkyl, —O(C)O—NHR¹⁰, —O(C)O—N(R¹⁰)R¹¹,—C(O)O-alkyl, —S(O)₂R¹⁰, —SR¹⁰, —S(O)₂NHR¹⁰, and —S(O)₂NR¹⁰R¹¹

In one embodiment, in Formula (I.a), n is 1; each R², R³, R⁵, R⁶, R⁸,R¹⁸ and R¹⁹ is H; R⁴ and R⁷ are OH; and R⁹ is methyl, wherein saidmethyl is unsubstituted or substituted with from one to three groupsindependently selected from —OH, halo, alkyl, —CN, —NH₂, —NHR¹⁶,—NR¹⁶R¹⁷, —NHS(O)₂R¹⁰, —N(R¹⁰)S(O)₂R¹⁰, -Oalkyl, -Ocycloalkyl,—O-alkyl-cycloalkyl, —OC(O)-alkyl, —O(C)O—NHR¹⁰, —O(C)O—N(R¹⁰)R¹¹,—C(O)O-alkyl, —S(O)₂R¹⁰, —SR¹⁰, —S(O)₂NHR¹⁰, and —S(O)₂NR¹⁰R¹¹.

In some embodiments, R⁹ is -alkyl-NHS(O)₂R¹⁰, wherein R¹⁰ is selectedfrom methyl, ethyl, and cyclopropyl.

In some embodiments, R⁹ is selected from -alkyl —N(CH₃)S(O)₂R¹⁰ and-alkyl-N(CH₂CH₃)S(O)₂R¹⁰, wherein R¹⁰ is selected from methyl, ethyl,and cyclopropyl.

In some embodiments, R⁹ is -alkyl-O(C)O—NHR¹⁰, wherein R¹⁰ is selectedfrom methyl, ethyl, and cyclopropyl.

In some embodiments, R⁹ is selected from R⁹-alkyl-O(C)O—N(CH₃)R¹⁰ and—O(C)O—N(CH₂CH₃)R¹⁰, wherein R¹⁰ is selected from methyl, ethyl, andcyclopropyl.

In one embodiment, in Formula (I.a), n is 1: R² is H; R⁴ and R⁷ are eachindependently selected from H and OH; R⁵ is selected from H, halo, andalkyl; and R⁹ is selected from H, —CH₃, —CH₂—CH₃, —CH₂—OH, —CH₂—O-alkyl,—CH₂—OC(O)-haloalkyl, —CH₂—NH₂, —CH₂—NHR¹⁶, and —CH₂—NR¹⁶R¹⁷.

In one embodiment, in Formula (I.a), n is 1, R² is H, R⁵ is —CH₃, and R⁹is selected from H, —CH₃, —CH₂—CH₃, —CH₂—OH, —CH₂—O-alkyl,—CH₂—OC(O)CF₃, —CH₂—NH₂, —CH₂—NHR¹⁶, and —CH₂—NR¹⁶R¹⁷.

In one embodiment, in Formula (I.a), n is 1; R² is H; R⁴ and R⁷ are each—OH, R⁵ is —CH₃, and R⁹ is H.

In one embodiment, in Formula (I.a), n is 1; R² is H; R⁴ and R⁷ are each—OH, R⁵ is selected from H and —CH₃, and R⁹ is selected from H, —OH,halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl,—O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹,—C(O)OH, —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰,—S(O)NR¹⁰R¹¹, —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰,

-   -   wherein each of said -alkyl, said -alkenyl, said alkynyl, said        aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said        —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally        independently substituted with from one to three substituents,        which can be the same or different, each substituent being        independently selected from halo, —OH, alkyl, haloalkyl,        heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl,        —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl,        —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl,        —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl,        —S(O)₂alkyl, —S-alkyl, —CN, —NH₂, —NHR¹⁶, and —N(alkyl)₂, aryl,        heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and        heterocycloalkenyl.

In one embodiment, in Formula (I.a), X is N, Y is N, n is 1; R² is H; R⁴and R⁷ are each —OH, R⁵ is selected from H and —CH₃, and R⁹ is selectedfrom H , -alkyl, -alkyl-OH, -alkyl-S(O)₂alkyl, -alkyl-5-alkyl,haloalkyl, heteroalkyl, -alkyl-CN, -alkyl-NH₂, -alkyl-NHR¹⁶, and-alkyl-N(alkyl)₂. In one such embodiment, each said alkyl is selectedfrom straight or branched lower alkyl.

In one embodiment, the compounds of the invention have the structuralFormula (I.a.1):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, and R² isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.1.i):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, and R² isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.2):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, and R² isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.2.i):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, and R² isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.3):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², and n isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.3.i)

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, and R² isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.4):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², and n isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.4.i):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, and R² isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.5):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², and n isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.5.i):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, and R² isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.6):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², and n isselected independently defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.6.i):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, and R² isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.7):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², and n isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.7.i):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, and R² isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.8):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², and n isselected independently defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.8.i):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, and R² isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.9):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², n, andR¹⁶ is selected independently defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.9.i):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², and R¹⁶is selected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.10):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², n, R¹⁶,and R¹⁷ is selected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.10.i):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², R¹⁶, andR¹⁷ is selected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.a.10.j):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, R², X, Y, Z, and isselected independently and defined in Formula (I), and wherein CB is amoiety selected from the group consisting of:

wherein each R¹⁰ is independently selected from the group consisting ofmethyl, ethyl, and cyclopropyl.

In one embodiment, in Formula (I.a.10.j):

X is N; Y is N; R² is H; and Z is selected from the group consisting ofH, methyl, and chloro; and R and R¹ are each as defined in Formula (I).In other such embodiments, R and R¹ are each independently as defined inany of the various embodiments described herein, or in the examples.

In one embodiment, in Formula (I.a.10.j):

X is N; Y is N; R² is H;

Z is selected from the group consisting of H, methyl, and chloro;

R is unsubstituted phenyl or phenyl substituted with from 1 to 4substituents independently selected from the group consisting of alkyl,alkoxy, cycloalkyl, halo, —CN, —NH₂, and —NO₂,

or, alternatively, R is unsubstituted heteroaryl or heteroarylsubstituted with from 1 to 3 substituents independently selected fromthe group consisting of alkyl, alkoxy, cycloalkyl, halo, —CN, —NH₂, and—NO₂; and

R¹ is selected from the group consisting of —NH₂, —NHR¹⁴, and —NR¹⁴R¹⁵,wherein R¹⁴ and R¹⁵ (when present) are each as defined in Formula I.

In one embodiment, in Formula (I.a.10.j):

X is N; Y is N; R² is H;

Z is selected from the group consisting of H, methyl, and chloro;

R is unsubstituted phenyl or phenyl substituted with from 1 to 4substituents independently selected from the group consisting of alkyl,alkoxy, halo, —CN, —NH₂, and —NO₂,

or, alternatively, R is unsubstituted pyridyl or pyridyl substitutedwith from 1 to 3 substituents independently selected from the groupconsisting of alkyl, alkoxy, halo, —CN, —NH₂, and —NO₂; and

R¹ is —NH₂.

In one embodiment, in Formula (I.a.10.j):

X is N; Y is N;

R² is H;

CB is a moiety having a formula:

Z is selected from the group consisting of H, methyl, and chloro;

R is unsubstituted phenyl or phenyl substituted with from 1 to 4substituents independently selected from the group consisting of alkyl,alkoxy, halo, —CN, —NH₂, and —NO₂,

or, alternatively, R is unsubstituted pyridyl or pyridyl substitutedwith from 1 to 3 substituents independently selected from the groupconsisting of alkyl, alkoxy, halo, —CN, —NH₂, and —NO₂; and

R¹ is —NH₂.

In one embodiment, the compounds of the invention have the structuralFormula (I.B):

and includes pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², R³, R⁴,R⁷, R⁸, R⁹, R¹⁸, R¹⁹, and n is selected independently and defined inFormula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.b):

and includes pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², and R⁹ isselected independently and defined in Formula (I).

In one embodiment, in Formula (I.b), R² is H, and R⁹ is selected from H,—CH₃, —CH₂—O-alkyl, —CH₂—OH, —CH₂—OC(O)-alkyl, —CH₂—OC(O)-haloalkyl,—CH₂—CH₃, —CH₂—NH₂, —CH₂—NHR¹⁶, and —CH₂—NR¹⁶R¹⁷.

In one embodiment, in Formula (I.b), R² is H, and R⁹ is selected from—CH₂—O-alkyl, and —CH₂—OH.

In one embodiment, the compounds of the invention have the structuralFormula (I.b.1):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, and R² isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.b.1.i):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, and R² isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.b.2):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², and n isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the Formula(I.b.2.i):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, and R² isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.C):

and includes pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², R³, R⁵,R⁶, R⁸, R⁹, R¹⁸, R¹⁹, R²⁰, R²¹, and n is selected independently anddefined in Formula (I), with the proviso that R⁵ and R⁶ are not takentogether to form a double bond.

In one embodiment, the compounds of the invention have the structuralFormula (I.c):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², R⁹, R²⁰,and R²¹ is selected independently and defined in Formula (I).

In one embodiment, in Formula (I.c), R² is H; R⁹ is selected from H,—CH₃, —CH₂—O-alkyl, —CH₂—OH, —CH₂—OC(O)-alkyl, —CH₂—OC(O)-haloalkyl,—CH₂—CH₃, —CH₂—NH₂, —CH₂—NHR¹⁶, and —CH₂—NR¹⁶R¹⁷; and each of R²⁰ andR²¹ is independently selected from H and —CH₃.

In one embodiment, the compounds of the invention have the structuralFormula (I.c.1):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, and R² isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.c.1.i):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, and R² isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.c.2):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², and n isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.c.2.i):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, and R² isselected independently defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.D):

and includes pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², R³, R⁵,R⁶, R⁸, R⁹, R¹⁸, and R¹⁹, and n is selected independently and defined inFormula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.d):

and includes pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², R⁹, and nis selected independently and defined in Formula (I).

In one embodiment, in Formula (I.d), n is 1 and R⁹ is selected from H,—CH₃, —CH₂—O-alkyl, —CH₂—OH, —CH₂—OC(O)-alkyl, —CH₂—OC(O)-haloalkyl,—CH₂—CH₃, —CH₂—NH₂, —CH₂—NHR¹⁶, and —CH₂—NR¹⁶R¹⁷.

In one embodiment, in Formula (I.d), n is 1 and R⁹ is selected from—CH₂—O-alkyl, and —CH₂—OH.

In one embodiment, the compounds of the invention have the structuralFormula (I.d.1):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, and R² isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.d.1.i):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, and R² isselected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (I.E):

and includes pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R², R³, R⁵,R⁶, R⁸, R⁹, R¹⁸, and R¹⁹, and n is selected independently and defined inFormula (I).

In one embodiment, the compounds of the invention have the structuralFormula (II):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, Z, R³, R⁴, R⁵,R⁶, R⁷, and R⁸ is selected independently and defined in Formula (I).

In one embodiment, the compounds of the invention have the structuralFormula (II):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, and Z isselected independently and wherein R, R¹, X, Y, and Z are defined inFormula (I).

In one embodiment, in Formula (I), the compounds of the invention havethe structural Formula (II.a.1):

and include pharmaceutically acceptable salts, esters, prodrugs, orisomers of said compounds, wherein each of R, R¹, X, Y, and Z isselected independently and wherein R, R¹, X, Y, and Z are defined inFormula (I).

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), X is N and Y is N.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), X is N and Y is CH.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), X is CH and Y is N.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.1), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R is selected from aryl, heteroaryl, benzo-fusedheteroaryl, cycloalkyl, cycloalkenyl, benzo-fused cycloalkyl,benzo-fused cycloalkenyl, heterocycloalkyl, and benzo-fusedheterocycloalkyl,

-   -   wherein each of said alkyl, said aryl, said heteroaryl, said        benzo-fused heteroaryl, said cycloalkyl, said cycloalkenyl, said        heterocycloalkyl, said heterocycloaklenyl, and said benzo-fused        heterocycloalkyl is unsubstituted or optionally independently        substituted with from one to five substituents, which are the        same or different, each substituent being independently selected        from halo, —OH, —CN, alkyl, cycloalkyl, alkenyl, alkynyl,        haloalkyl, heteroalkyl, heterohaloalkyl, -alkyl-OH, —O-alkyl,        —O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl,        —O-alkyl-aryl, —S-alkyl-aryl, heteroaryl, —O-heteroaryl,        —S-heteroaryl, —O-alkyl-heteroaryl, —S-alkyl-heteroaryl,        heterocycloalkyl, —C(O)-alkyl, —C(O)-haloalkyl, —C(O)H, —C(O)OH,        —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹,        —C(O)ONH₂, —C(O)ONHR¹⁰, —C(O)ONR¹⁰R¹¹, —NH₂, —NHR¹⁰, —NR¹⁰R¹¹,        —NO₂, substituted aryl, and substituted heteroaryl, wherein each        of said substituted aryl and said substituted heteroaryl        independently contains from one to three substituents, which may        be the same or different, each substituent being independently        selected from halo, alkyl, —O-alkyl, and —C(O)Oalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.1.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R is selected from the group consisting ofsubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, and substituted or unsubstituted benzo-fused heteroaryl,each of said substituents being independently selected from the groupconsisting of alkyl, —O-alkyl, and cycloalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R is selected from substituted alkynyl,substituted alkynyl, unsubstituted aryl, substituted aryl, unsubstitutedcycloalkyl, substituted cycloalkyl, unsubstituted benzo-fusedcycloalkyl, substituted benzo-fused cycloalkyl, unsubstitutedcycloalkenyl, and substituted cycloalkenyl, which substituents, whenpresent, are as defined in Formula (I).

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R is unsubstituted aryl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R is substituted aryl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R is unsubstituted cycloalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R is unsubstituted benzo-fused cycloalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R is substituted benzo-fused cycloalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R is substituted cycloalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R is unsubstituted cycloalkenyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R is substituted cycloalkenyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R is selected from unsubstituted heteroaryl,substituted heteroaryl, unsubstituted benzo-fused heteroaryl,substituted benzo-fused heteroaryl, unsubstituted heterocycloalkyl,substituted heterocycloalkyl, unsubstituted benzo-fusedheterocycloalkyl, substituted benzo-fused heterocycloalkyl,unsubstituted heterocycloalkenyl, and unsubstituted heterocycloalkenyl,which substituents, when present, are as defined in Formula (I).

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R is unsubstituted heteroaryl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i), (I.a.5),(I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8), (I.a.8.i),(I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1), (I.b.1.i),(I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i), (I.c.2),(I.c.2.i), (I.D), (Id), (I.d.1), (I.d.1.i), (I.E), (II), (II.A), and(II.A.1), R is substituted heteroaryl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8), (I.a.8.i),(I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1), (I.b.1.i),(I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i), (I.c.2),(I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II), (II.A), and(II.A.1), R is unsubstituted benzo-fused heteroaryl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R is substituted benzo-fused heteroaryl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.4), (I.a.4.i), (I.a.5),(I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8), (I.a.8.i),(I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1), (I.b.1.i),(I.b.2), (I.C), (I.c), (I.c.1), (I.c.1.i), (I.c.2), (I.c.2.i), (I.D),(I.d), (I.d.1), (I.d.1.i), (I.E), (II), (II.A), and (II.A.1), R isunsubstituted heterocycloalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i), (I.a.5),(I.a.5.i), (I.a.6), (I.a.7), (I.a.7.i), (I.a.8), (I.a.8.i), (I.a.10),(I.ai 0.1), (I.a.10.j), (I.B), (I.b), (I.b.1), (I.b.1.i), (I.b.2),(I.C), (I.c), (I.c.1), (I.c.1.i), (I.c.2), (I.c.2.i), (I.D), (I.d),(I.d.1), (I.d.1.i), (I.E), (II), (II.A), and (II.A.1), R is substitutedheterocycloalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.ai .i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R is unsubstituted benzo-fused heterocycloalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.1), (I.a.2), (I.a.2.i), (I.a.3), (I.a.4), (I.a.4.i), (I.a.5),(I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8), (I.a.8.i),(I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1), (I.b.1.i),(I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i), (I.c.2),(I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II), (II.A), and(II.A.1), R is substituted benzo-fused heterocycloalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R is unsubstituted heterocycloalkenyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.1.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R is substituted heterocycloalkenyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1i),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8), (I.a.8.i),(I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1), (I.b.1.i),(I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i), (I.c.2),(I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II), (II.A), and(II.A.1), R is an unsubstituted or substituted monocyclic aryl moiety oran unsubstituted or substituted heteroaryl moiety. Non-limiting examplesof such unsubstituted or substituted monocyclic aryl moiety orunsubstituted or substituted heteroaryl moiety include:

wherein the wavy line represents the point of attachment of R to therest of the molecule, and wherein each of R_(a), R_(b), R_(d), andR_(e), is independently selected from H, halo, —OH, —CN, alkyl,cycloalkyl, haloalkyl, -alkyl-OH, heteroalkyl, heterohaloalkyl,—O-alkyl, —O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl,—O-alkyl-aryl, —S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl,—O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-alkyl,—C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH₂,—C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —C(O)ONH₂, —C(O)ONHR¹⁰, —C(O)ONR¹⁰R¹¹, —NH₂,—NHR¹⁰, —NR¹⁰R¹¹, —NO₂, substituted aryl, and substituted heteroaryl,wherein each of said substituted aryl and said substituted heteroarylindependently contains from one to three substituents, which may be thesame or different, each substituent being independently selected fromhalo, alkyl, —O-alkyl, and —C(O)Oalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R is an unsubstituted or an substituted bicyclicheteroaryl moiety. Non-limiting examples of such unsubstituted orsubstituted bicyclic heteroaryl moieties include:

wherein the wavy line represents the point of attachment of R to therest of the molecule, and wherein each of R_(a), R_(b), R_(c), R_(d),and R_(e), is independently selected from H, halo, —OH, —CN, alkyl,cycloalkyl, haloalkyl, -alkyl-OH, heteroalkyl, heterohaloalkyl,—O-alkyl, —O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl,—O-alkyl-aryl, —S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl,—O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-alkyl,—C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH₂,—C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —C(O)ONH₂, —C(O)ONHR¹⁰, —C(O)ONR¹⁰R¹¹, —NH₂,—NHR¹⁰, —NR¹⁰R¹¹, —NO₂, substituted aryl, and substituted heteroaryl,wherein each of said substituted aryl and said substituted heteroarylindependently contains from one to three substituents, which may be thesame or different, each substituent being independently selected fromhalo, alkyl, —O-alkyl, and —C(O)Oalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is selected from the group consisting of halo,alkyl, haloalkyl, cycloalkyl, and —NH₂. Non-limiting examples of Z whenZ is cycloalkyl include cyclopropyl. Non-limiting examples of Z when Zis haloalkyl include fluoroalkyl (up to perfluoroalkyl).

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is selected from the group consisting of halo,alkyl, and cycloalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is H.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is halo.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is —Cl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is —F.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is —OH.

In other embodiments, in each of Formulas (I), (I.A), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is —SH.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is —Salkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is —S—CH₃.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is -alkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.1), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.1), (I.E), (II),(II.A), and (II.A.1), Z is —CH₃.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.1), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is —CH₂CH₃.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is —Oalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is —OCH₃.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i), (I.a.5),(I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8), (I.a.8.i),(I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1), (I.b.1.i),(I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i), (I.c.2),(I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II), (II.A), and(II.A.1), Z is -haloalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is —CF₃.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is —CHF₂.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is —CH₂F.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is cycloalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is cyclopropyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is aryl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is phenyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is heteroaryl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is 2-thiophenyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.4), (I.a.4.i), (I.a.5),(I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8), (I.a.8.i),(I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1), (I.b.1.i),(I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i), (I.c.2),(I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II), (II.A), and(II.A.1), Z is 3-thiophenyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is 2-thiazolyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is 2-oxazolyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is 2-pyrimidinyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is 2-pyridyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is 2-pyrazinyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is 2-imidazolyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is —NH₂.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is —NHR².

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is —NR¹²R¹³.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is selected from the group consisting of Cl andmethyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is selected from the group consisting of —NH₂,—NHR¹⁴, and —NR¹⁴R¹⁵.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is selected from the group consisting of —NH₂and —NHR¹⁴.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is H.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is halo.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is Cl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is F.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is alkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is —CH₃.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is —CH₂CH₃.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.1),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is heteroalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is heteroaryl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.1.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is —OH.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is —O-alkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d.1), (I.d.1.i), (I.E), (II), (II.A), and(II.A.1), R¹ is —O-aryl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is —O-heteroalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is —O-heteroaryl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is —SH.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is —S-alkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1), (I.b.1.i),(I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i), (I.c.2),(I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II), (II.A), and(II.A.1), R¹ is —S-aryl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.1),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is —S-heteroalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.5), (I.a.5.i),(I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8), (I.a.8.i), (I.a.10),(I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1), (I.b.1.i), (I.b.2),(I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i), (I.c.2), (I.c.2.i), (I.D),(I.d), (I.d.1), (I.d.1.i), (I.E), (II), (II.A), and (II.A.1), R¹ is—S-heteroaryl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is —NH₂.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.5),(I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8), (I.a.8.i),(I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1), (I.b.1.i),(I.b.2), (I.C), (I.c), (I.c.1), (I.c.1.i), (I.c.2), (I.c.2.i), (I.D),(I.d), (I.d.1), (I.d.1.i), (I.E), (II), (II.A), and (II.A.1), R¹ is—NHR¹⁴. Non-limiting examples of R¹ when R¹ is —NHR¹⁴ include:

wherein the wavy line represents the point of attachment of R¹ to therest of the molecule, and wherein each R_(aa) is independently selectedfrom haloalkyl (non-limiting examples of which include —CH₂F, —CHF₂,—CF₃, etc.), R_(ab) is selected from OH, OAc, and —O-alkyl (non-limitingexamples of which include —O-Me, —O-Et, —O-n-Pr, —O-i-Pr, —O-n-Bu,—O-1-Bu, and —O-t-Bu), —O-haloalkyl (non-limiting examples of whichinclude —O—CH₂F, —O—CHF₂, and —O—CF₃), —NH₂, —NHalkyl, and —N(alkyl)₂.

Additional non-limiting examples of R¹ when R¹ is —NHR¹⁴ include:

wherein the wavy line represents the point of attachment of R¹ to therest of the molecule, and wherein R_(af) is selected from H and acetyl.It shall be understood that positional isomers of the heteroatoms shownin the moieties above are also contemplated. Such positional isomersinclude symmetric positional isomers such as

Additional non-limiting examples of R¹ when R¹ is —NHR¹⁴ include:

wherein the wavy line represents the point of attachment of R¹ to therest of the molecule, and wherein each of R_(a), R_(b), R_(c), R_(d),and R_(e), is independently selected from H, halo, —OH, —CN, alkyl,haloalkyl, -alkyl-OH, heteroalkyl, heterohaloalkyl, —O-alkyl,—O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl,—S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl,—O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-alkyl,—C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH₂,—C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —C(O)ONH₂, —C(O)ONHR¹⁰, —C(O)ONR¹⁰R¹¹, —NH₂,—NHR¹⁰—NR¹⁰R¹¹, —NO₂, substituted aryl, and substituted heteroaryl,wherein each of said substituted aryl and said substituted heteroarylindependently contains from one to three substituents, which may be thesame or different, each substituent being independently selected fromhalo, alkyl, alkyl, and —C(O)Oalkyl, and wherein each R_(ad) and eachR_(ae) is independently selected from alkyl and haloalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), R¹ is —NR¹⁴R¹⁵. Non-limiting examples of R¹ whenR¹ is —NR¹⁴R¹⁵ include:

wherein the wavy line represents the point of attachment of R¹ to therest of the molecule, and wherein each R_(aa) is independently selectedfrom haloalkyl (non-limiting examples of which include —CH₂F, —CHF₂,—CF₃, etc.), R_(ab) is selected from OH, OAc, and —O-alkyl (non-limitingexamples of which include —O-Me, —O-Et, —O-n-Pr, —O-i-Pr, —O-n-Bu,—O-i-Bu, and —O-t-Bu), —O-haloalkyl (non-limiting examples of whichinclude —O—CH₂F, —O—CHF₂, and —O—CF₃), —NH₂, —NHalkyl, and —N(alkyl)₂.

Additional non-limiting examples of R¹ when R¹ is —NR¹³R¹⁵ include:

wherein the wavy line represents the point of attachment of R¹ to therest of the molecule, and wherein R_(af) is selected from H and acetyl.It shall be understood that positional isomers of the heteroatoms shownin the moieties above are also contemplated. Such positional isomersinclude symmetric positional isomers such as

Additional non-limiting examples of R¹ when R¹ is —Nee include:

wherein the wavy line represents the point of attachment of R¹ to therest of the molecule, and wherein each of R_(a), R_(b), R_(c), R_(d),and R_(e), is independently selected from H, halo, —OH, —CN, alkyl,haloalkyl, -alkyl-OH, heteroalkyl, heterohaloalkyl, —O-alkyl,—O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl,—S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl,—O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-alkyl,—C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH₂,—C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —C(O)ONH₂, —C(O)ONHR¹⁰, —C(O)ONR¹⁰R¹¹, —NH₂,—NHR¹⁰, —NR¹⁰R¹¹, —NO₂, substituted aryl, and substituted heteroaryl,wherein each of said substituted aryl and said substituted heteroarylindependently contains from one to three substituents, which may be thesame or different, each substituent being independently selected fromhalo, alkyl, alkyl, and —C(O)Oalkyl, and wherein each R_(ad) R_(ad) andeach R_(ae) is independently selected from alkyl and haloalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.j), (I.B), (I.b), (I.b.1), (I.b.1.i),(I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i), (I.c.2),(I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II), (II.A), and(II.A.1), R¹ is —NR¹⁴R¹⁵, wherein R¹⁴ and R¹⁵ are linked together withthe nitrogen to which they are attached to form an unsubstituted orsubstituted 4- to 6-membered heterocycloalkyl. Non-limiting examples ofR¹ when R¹ is —NR¹⁴R¹⁵ and R¹⁴ and R¹⁵ are so linked include:

wherein X is selected from O, NH, and NMe.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1):

R is selected from aryl, heteroaryl, benzo-fused heteroaryl, cycloalkyl,cycloalkenyl, benzo-fused cycloalkyl, benzo-fused cycloalkenyl,heterocycloalkyl, and benzo-fused heterocycloalkyl,

-   -   wherein each of said alkyl, said aryl, said heteroaryl, said        benzo-fused heteroaryl, said cycloalkyl, said cycloalkenyl, said        heterocycloalkyl, said heterocycloaklenyl, and said benzo-fused        heterocycloalkyl is unsubstituted or optionally independently        substituted with from one to three substituents, which are the        same or different, each substituent being independently selected        from halo, —OH, —CN, alkyl, alkenyl, alkynyl, haloalkyl,        heteroalkyl, heterohaloalkyl, -alkyl-OH, —O-alkyl, —O-haloalkyl,        —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl,        —S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl,        —O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl,        —C(O)-alkyl, —C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl,        —OC(O)-alkyl, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —C(O)ONH₂,        —C(O)ONHR¹⁰, —C(O)ONR¹⁰R¹¹, —NH₂, —NHR¹⁰, —NR¹⁰R¹¹, —NO₂,        substituted aryl, and substituted heteroaryl, wherein each of        said substituted aryl and said substituted heteroaryl        independently contains from one to three substituents, which may        be the same or different, each substituent being independently        selected from halo, alkyl, —O-alkyl, and —C(O)Oalkyl;    -   R¹ is selected from —NH₂, —NHR¹⁴, and —NR¹⁴R¹⁵; and    -   Z is selected from H, halo, alkyl, —OH, haloalkyl, and        cycloalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1):

R is

wherein the wavy line represents the point of attachment of R to therest of the molecule, and wherein each of R_(a), R_(b), R_(c), R_(d),and R_(e), is independently selected from H, halo, —OH, —CN, alkyl,haloalkyl, -alkyl-OH, heteroalkyl, heterohaloalkyl, —O-alkyl,—O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl,—S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl,—O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-alkyl,—C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH₂,—C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —C(O)ONH₂, —C(O)ONHR¹⁰, —C(O)ONR¹⁰R¹¹, —NH₂,—NHR¹⁰, —NR¹⁰R¹¹, —NO₂, substituted aryl, and substituted heteroaryl,wherein each of said substituted aryl and said substituted heteroarylindependently contains from one to three substituents, which may be thesame or different, each substituent being independently selected fromhalo, alkyl, —O-alkyl, and —C(O)Oalkyl;

-   -   R¹ is selected from —NH₂, —NHR¹⁴, and —NR¹⁴R¹⁵; and    -   Z is selected from H, halo, alkyl, —OH, haloalkyl, and        cycloalkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is halo; R¹ is selected from —NH₂, —NHR¹⁴, and—NR¹⁴R¹⁵; and R is as defined in claim 1.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is heteroaryl; R¹ is selected from —NH₂, —NHR¹⁴,and —NR¹⁴R¹⁵; and R is as defined in claim 1.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is H; R¹ is selected from —NH₂, —NHR¹⁴, and—NR¹⁴R¹⁵; and R is as defined in claim 1.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is alkyl; R¹ is selected from —NH₂, —NHR¹⁴, and—NR¹⁴R¹⁵; and R is as defined in claim 1.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is halo; R¹ is selected from —NH₂, —NHR¹⁴, and—NR¹⁴R¹⁵; and R is heteroaryl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.5),(I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8), (I.a.8.i),(I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1), (I.b.1.i),(I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i), (I.c.2),(I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II), (II.A), and(II.A.1), Z is heteroaryl; R¹ is selected from —NH₂, —NHR¹⁴, and—NR¹⁴R¹⁵; and R is heteroaryl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.8), (I.a.8.i), (I.a.10), (I.a.10.i),(I.a.10.j), (I.B), (I.b), (I.b.1), (I.b.1.i), (I.b.2), (I.b.2.i), (I.C),(I.c), (I.c.1), (I.c.1.i), (I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1),(I.d.1.i), (I.E), (II), (II.A), and (II.A.1), Z is H; R¹ is selectedfrom —NH₂, —NHR¹⁴, and —NR¹⁴R¹⁵; and R is heteroaryl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), Z is alkyl; R¹ is selected from —NH₂, —NHR¹⁴, and—Nee; and R is heteroaryl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1), X and Y are each N; R is selected fromunsubstituted aryl, substituted aryl, unsubstituted heteroaryl, andsubstituted heteroaryl, wherein said substituents, when present, aredefined in Formula (I); Z is selected from halo, —OH, —SH, alkyl, —NH₂,—NHR¹², and —NR¹²R¹³; R¹ is selected from —NH₂, —NHR¹⁴, and -Nee; and R²is selected from H and alkyl.

In other embodiments, in each of Formulas (I), (I.A), (I.a), (I.a.1),(I.a.1.i), (I.a.2), (I.a.2.i), (I.a.3), (I.a.3.i), (I.a.4), (I.a.4.i),(I.a.5), (I.a.5.i), (I.a.6), (I.a.6.i), (I.a.7), (I.a.7.i), (I.a.8),(I.a.8.i), (I.a.10), (I.a.10.i), (I.a.10.j), (I.B), (I.b), (I.b.1),(I.b.1.i), (I.b.2), (I.b.2.i), (I.C), (I.c), (I.c.1), (I.c.1.i),(I.c.2), (I.c.2.i), (I.D), (I.d), (I.d.1), (I.d.1.i), (I.E), (II),(II.A), and (II.A.1):

X is N;

Y is N;

R is selected from the group consisting of:

(a) an unsubstituted or substituted monocyclic aryl moiety or anunsubstituted or substituted heteroaryl moiety selected from the groupconsisting of:

wherein the wavy line represents the point of attachment of R to therest of the molecule, and wherein each of R_(a), R_(b), R_(c), R_(d),and R_(e), is independently selected from H, halo, —OH, —CN, alkyl,haloalkyl, -alkyl-OH, heteroalkyl, heterohaloalkyl, —O-alkyl,—O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl,—S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl,—O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-alkyl,—C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH₂,—C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —C(O)ONH₂, —C(O)ONHR¹⁰, —C(O)ONR¹⁰R¹¹, —NH₂,—NHR¹⁰, —NR¹⁰R¹¹, —NO₂, substituted aryl, and substituted heteroaryl,wherein each of said substituted aryl and said substituted heteroarylindependently contains from one to three substituents, which may be thesame or different, each substituent being independently selected fromhalo, alkyl, —O-alkyl, and —C(O)Oalkyl, and

(b) an unsubstituted or an substituted bicyclic heteroaryl moietyselected from the group consisting of:

wherein the wavy line represents the point of attachment of R to therest of the molecule, and wherein each of R_(a), R_(b), R_(c), R_(d),and R_(e), is independently selected from H, halo, —OH, —CN, alkyl,haloalkyl, -alkyl-OH, heteroalkyl, heterohaloalkyl, —O-alkyl,—O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl,—S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl,—O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-alkyl,—C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH₂,—C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —C(O)ONH₂, —C(O)ONHR¹⁰, —C(O)ONR¹⁰R¹¹, —NH₂,—NHR¹⁰, —NR¹⁰R¹¹, —NO₂, substituted aryl, and substituted heteroaryl,wherein each of said substituted aryl and said substituted heteroarylindependently contains from one to three substituents, which may be thesame or different, each substituent being independently selected fromhalo, alkyl, —O-alkyl, and —C(O)Oalkyl;

R¹ is selected from the group consisting of:

(a) —NH₂,

wherein the wavy line represents the point of attachment of R¹ to therest of the molecule, and wherein each R_(aa) is independently selectedfrom haloalkyl (non-limiting examples of which include —CH₂F, —CHF₂,—CF₃, etc.), R_(ab) is selected from OH, OAc, and —O-alkyl (non-limitingexamples of which include —O-Me, —O-Et, —O-n-Pr, —O-i-Pr, —O-n-Bu,—O-1-Bu, and —O-t-Bu), —O-haloalkyl (non-limiting examples of whichinclude —O—CH₂F, —O—CHF₂, and —O—CF₃), —NH₂, —NHalkyl, and —N(alkyl)₂,

wherein the wavy line represents the point of attachment of R¹ to therest of the molecule, and wherein R_(af) is selected from H and acetyl,

wherein the wavy line represents the point of attachment of R¹ to therest of the molecule, and wherein each of R_(a), R_(b), R_(c), R_(d),and R_(e), is independently selected from H, halo, —OH, —CN, alkyl,haloalkyl, -alkyl-OH, heteroalkyl, heterohaloalkyl, —O-alkyl,—O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl,—S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl,—O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-alkyl,—C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH₂,—C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —C(O)ONH₂, —C(O)ONHR¹⁰, —C(O)ONR¹⁰R¹¹, —NH₂,—NHR¹⁰, —NR¹⁰R¹¹, —NO₂, substituted aryl, and substituted heteroaryl,wherein each of said substituted aryl and said substituted heteroarylindependently contains from one to three substituents, which may be thesame or different, each substituent being independently selected fromhalo, alkyl, —O-alkyl, and —C(O)Oalkyl, and wherein each R_(ad) R_(ad)and each R_(ae) is independently selected from alkyl and haloalkyl,

wherein the wavy line represents the point of attachment of R¹ to therest of the molecule, and wherein each R_(aa) is independently selectedfrom haloalkyl (non-limiting examples of which include —CH₂F, —CHF₂,—CF₃, etc.), R_(ab) is selected from OH, OAc, and —O-alkyl (non-limitingexamples of which include —O-Me, —O-Et, —O-n-Pr, —O-i-Pr, —O-n-Bu,—O-1-Bu, and —O-t-Bu), —O-haloalkyl (non-limiting examples of whichinclude —O—CH₂F, —O—CHF₂, and —O—CF₃), —NH₂, —NHalkyl, and —N(alkyl)₂,

wherein the wavy line represents the point of attachment of R¹ to therest of the molecule, and wherein R_(af) is selected from H and acetyl,

wherein the wavy line represents the point of attachment of R¹ to therest of the molecule, and wherein each of R_(a), R_(b), R_(c), R_(d),and R_(e), is independently selected from H, halo, —OH, —CN, alkyl,haloalkyl, -alkyl-OH, heteroalkyl, heterohaloalkyl, —O-alkyl,—O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl,—S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl,—O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-alkyl,—C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH₂,—C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —C(O)ONH₂, —C(O)ONHR¹⁰, —C(O)ONR¹⁰R¹¹, —NH₂,—NHR¹⁰, —NR¹⁰R¹¹, —NO₂, substituted aryl, and substituted heteroaryl,wherein each of said substituted aryl and said substituted heteroarylindependently contains from one to three substituents, which may be thesame or different, each substituent being independently selected fromhalo, alkyl, —O-alkyl, and —C(O)Oalkyl, and wherein each R_(ad) R_(ad)and each R_(ae) is independently selected from alkyl and haloalkyl, and

wherein X is selected from O, NH, and NMe; and

-   -   Z is selected from the group consisting of H, halo, —OH, —SH,        —CN, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl,        heterohaloalkyl, —S-alkyl, —O-alkyl, —O-aryl, —O-heteroaryl,        cycloalkyl, aryl, heteroaryl, —NH₂, —NHR¹², and —NR¹²R¹³.

In other embodiments, the compounds of the invention have a structuralformula as depicted in Table I below and include tautomers, andpharmaceutically acceptable salts, esters, prodrugs, isomers, andsolvates of such compounds and such tautomers.

DEFINITIONS

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names and chemical structures may be used interchangeablyto describe that same structure. These definitions apply regardless ofwhether a term is used by itself or in combination with other terms,unless otherwise indicated. Hence the definition of “alkyl” applies to“alkyl” as well as the “alkyl” protion of “hydroxyalkyl”, “haloalkyl”,arylalkyl-, alkylaryl-, “alkoxy” etc.

“At least one” means one or more than one, for example, 1, 2, or 3, orin another example, 1 or 2, or in another example 1.

“One or more” means one or more than one, for example, 1, 2, or 3, or inanother example, 1 or 2, or in another example 1.

“Patient” includes both human and non-human animals. Non-human animalsinclude research animals, farm animals, and companion animals such asmice, primates, monkeys, great apes, cows, sheep, horse, canine (e.g.,dogs), and feline (e.g., house cats), etc.

“Composition” includes “pharmaceutical composition” and othercompositions not suitable for phainiaceutical use but which may besuitable for other uses such as research or other uses.

“Pharmaceutical composition” (or “pharmaceutically acceptablecomposition”) means a composition suitable for administration to apatient. Such compositions may contain the neat compound (or compounds)of the invention or mixtures thereof, or salts, solvates, prodrugs,isomers, or tautomers thereof, or they may contain one or morepharmaceutically acceptable carriers or diluents. The term“pharmaceutical composition” is also intended to encompass both the bulkcomposition and individual dosage units comprised of more than one(e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional agent selected fromthe lists of the additional agents described herein, along with anypharmaceutically inactive excipients. The bulk composition and eachindividual dosage unit can contain fixed amounts of the afore-said “morethan one pharmaceutically active agents”. The bulk composition ismaterial that has not yet been formed into individual dosage units. Anillustrative dosage unit is an oral dosage unit such as tablets, pillsand the like. Similarly, the herein-described method of treating apatient by administering a pharmaceutical composition of the presentinvention is also intended to encompass the administration of theafore-said bulk composition and individual dosage units.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine and bromine.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched.

“Alkyl” may be unsubstituted or optionally substituted by one or moresubstituents which may be the same or different, each substituent beingas described herein or independently selected from the group consistingof halo, alkyl, haloalkyl, spirocycloalkyl, aryl, cycloalkyl, cyano,hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl),—O—C(O)-alkyl, —O—C(O)-aryl, —O—C(O)-cycloalkyl, carboxy and—C(O)O-alkyl. Non-limiting examples of suitable alkyl groups includemethyl, ethyl, n-propyl, isopropyl and t-butyl.

“Haloalkyl” means an alkyl as defined above wherein one or more hydrogenatoms on the alkyl is replaced by a halo group defined above.

“Aminoalkyl” means an alkyl which has been substituted at one or moreavailable carbon atoms by one or more amino group(s). Non-limitingexamples of such amino groups include those described herein, such as—NH₂, —NHR¹², —NR¹²R¹³, —NHR¹⁴, and —NHR¹⁵.

“Heteroalkyl” means an alkyl moiety as defined above, having one or morecarbon atoms, for example one, two or three carbon atoms, including aterminal carbon atom, replaced with one or more heteroatoms, which maybe the same or different, where the point of attachment to the remainderof the molecule is through a carbon atom of the heteroalkyl radical.Suitable such heteroatoms include O, S, S(O), S(O)₂, —NH—, —N(alkyl)-,and —N(alkyl)₂. Non-limiting examples include ethers, thioethers,amines, hydroxymethyl, 3-hydroxypropyl, 1,2-dihydroxyethyl,2-methoxyethyl, 2-aminoethyl, 2-dimethylaminoethyl, and the like.Additional non-limiting examples include -alkyl-NHalkyl and-alkyl-N(alkyl)₂. A non-limiting example of heteroalkyl wherein aterminal carbon atom is replaced with a heteroatom includes -alkyl-NH₂.

“Heterohaloalkyl” means an haloalkyl moiety as defined above, having oneor more, for example one, two, or three carbon atoms, including aterminal carbon atom, replaced with one or more heteroatoms, which maybe the same or different, where the point of attachment to the remainderof the molecule is through a carbon atom of the heterohaloalkyl radical.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. “Alkenyl” may be unsubstituted or optionally substituted byone or more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, alkyl, aryl, cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkylene” means a difunctional group obtained by removal of a hydrogenatom from an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene, ethylene and propylene. More generally, thesuffix “ene” on alkyl, aryl, heterocycloalkyl, etc. indicates a divalentmoiety, e.g., —CH₂CH₂— is ethylene, and

is para-phenylene.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. “Alkynyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of alkyl, aryl and cycloalkyl.

“Alkenylene” means a difunctional group obtained by removal of ahydrogen from an alkenyl group that is defined above. Non-limitingexamples of alkenylene include —CH═CH—, —C(CH₃)═CH—, and —CH═CHCH₂—.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. “Heteroaryl”may also include a heteroaryl as defined above fused to an aryl asdefined above. Non-limiting examples of suitable heteroaryls includepyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (includingN-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl,pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined herein. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like. Furthernon-limiting examples of cycloalkyl include the following:

“Spirocycloalkyl” means a cycloalkyl moiety in which two availablehydrogen atoms attached to the same carbon atom are replaced to form acycloalkyl group.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedabove. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and thelike. Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

“Heterocycloalkyl” (or “heterocyclyl”) means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur, alone or in combination. Thereare no adjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls contain about 5 to about 6 ring atoms. Theprefix aza, oxa or thia before the heterocyclyl root name means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. Any —NH in a heterocyclyl ring may exist protected such as,for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like; suchprotections are also considered part of this invention. The heterocyclylcan be optionally substituted by one or more “ring system substituents”which may be the same or different, and are as defined herein. Thenitrogen or sulfur atom of the heterocyclyl can be optionally oxidizedto the corresponding N-oxide, S-oxide or S,S-dioxide. Thus, the term“oxide,” when it appears in a definition of a variable in a generalstructure described herein, refers to the corresponding N-oxide,S-oxide, or S,S-dioxide. Non-limiting examples of suitable monocyclicheterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.“Heterocyclyl” also includes rings wherein ═O replaces two availablehydrogens on the same carbon atom (i.e., heterocyclyl includes ringshaving a carbonyl group in the ring). Such ═O groups may be referred toherein as “oxo.” An example of such a moiety is pyrrolidinone (orpyrrolidone):

“Heterocycloalkenyl” (or “heterocyclenyl”) means a non-aromaticmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur atom, alone or in combination,and which contains at least one carbon-carbon double bond orcarbon-nitrogen double bond. There are no adjacent oxygen and/or sulfuratoms present in the ring system. Preferred heterocyclenyl rings containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclenyl root name means that at least a nitrogen, oxygen orsulfur atom respectively is present as a ring atom. The heterocyclenylcan be optionally substituted by one or more ring system substituents,wherein “ring system substituent” is as defined above. The nitrogen orsulfur atom of the heterocyclenyl can be optionally oxidized to thecorresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples ofsuitable heterocyclenyl groups include 1,2,3,4-tetrahydropyridinyl,1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl”also includes rings wherein ═O replaces two available hydrogens on thesame carbon atom (i.e., heterocyclyl includes rings having a carbonylgroup in the ring). Example of such moiety is pyrrolidenone (orpyrrolone):

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms of the compounds of theinvention are also contemplated as being within the scope of theinvention.

“Arylcycloalkyl” (or “arylfused cycloalkyl”) means a group derived froma fused aryl and cycloalkyl as defined herein. Preferred arylcycloalkylsare those wherein aryl is phenyl (which may be referred to as“benzofused”) and cycloalkyl consists of about 5 to about 6 ring atoms.The arylcycloalkyl can be optionally substituted as described herein.Non-limiting examples of suitable arylcycloalkyls include indanyl (abenzofused cycloalkyl) and 1,2,3,4-tetrahydronaphthyl and the like. Thebond to the parent moiety is through a non-aromatic carbon atom.

“Arylheterocycloalkyl” (or “arylfused heterocycloalkyl”) means a groupderived from a fused aryl and heterocycloalkyl as defined herein.Preferred arylheterocycloalkyls are those wherein aryl is phenyl (whichmay be referred to as “benzofused”) and heterocycloalkyl consists ofabout 5 to about 6 ring atoms. The arylheterocycloalkyl can beoptionally substituted, and/or contain the oxide or oxo, as describedherein. Non-limiting examples of suitable arylfused heterocycloalkylsinclude:

The bond to the parent moiety is through a non-aromatic carbon atom.

It is also understood that the terms “arylfused aryl”, “arylfusedcycloalkyl”, “arylfused cycloalkenyl”, “arylfused heterocycloalkyl”,arylfused heterocycloalkenyl”, “arylfused heteroaryl”, “cycloalkylfusedaryl”, “cycloalkylfused cycloalkyl”, “cycloalkylfused cycloalkenyl”,“cycloalkylfused heterocycloalkyl”, “cycloalkylfusedheterocycloalkenyl”, “cycloalkylfused heteroaryl, “cycloalkenylfusedaryl”, “cycloalkenylfused cycloalkyl”, “cycloalkenylfused cycloalkenyl”,“cycloalkenylfused heterocycloalkyl”, “cycloalkenylfusedheterocycloalkenyl”, “cycloalkenylfused heteroaryl”,“heterocycloalkylfused aryl”, “heterocycloalkylfused cycloalkyl”,“heterocycloalkylfused cycloalkenyl”, “heterocycloalkylfusedheterocycloalkyl”, “heterocycloalkylfused heterocycloalkenyl”,“heterocycloalkylfused heteroaryl”, “heterocycloalkenylfused aryl”,“heterocycloalkenylfused cycloalkyl”, “heterocycloalkenylfusedcycloalkenyl”, “heterocycloalkenylfused heterocycloalkyl”,“heterocycloalkenylfused heterocycloalkenyl”, “heterocycloalkenylfusedheteroaryl”, “heteroarylfused aryl”, “heteroarylfused cycloalkyl”,“heteroarylfused cycloalkenyl”, “heteroarylfused heterocycloalkyl”,“heteroarylfused heterocycloalkenyl”, and “heteroarylfused heteroaryl”are similarly represented by the combination of the groups aryl,cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, andheteroaryl, as previously described. Any such groups may beunsubstituted or substituted with one or more ring system substituentsat any available position as described herein.

“Aralkyl” or “arylalkyl” means an aryl-alkyl-group in which the aryl andalkyl are as previously described. Preferred aralkyls comprise a loweralkyl group. Non-limiting examples of suitable aralkyl groups includebenzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parentmoiety is through the alkyl. The term (and similar terms) may be writtenas “arylalkyl-” to indicate the point of attachment to the parentmoiety.

Similarly, “heteroarylalkyl”, “cycloalkylalkyl”, “cycloalkenylalkyl”,“heterocycloalkylalkyl”, “heterocycloalkenylalkyl”, etc., mean aheteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, etc. as described herein bound to a parent moietythrough an alkyl group. Preferred groups contain a lower alkyl group.Such alkyl groups may be straight or branched, unsubstituted and/orsubstituted as described herein.

Similarly, “arylfused arylalkyl-”, arylfused cycloalkylalkyl-, etc.,means an arylfused aryl group, arylfused cycloalkyl group, etc. linkedto a parent moiety through an alkyl group. Preferred groups contain alower alkyl group. Such alkyl groups may be straight or branched,unsubstituted and/or substituted as described herein.

“Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are aspreviously described. Preferred alkylaryls comprise a lower alkyl group.Non-limiting example of a suitable alkylaryl group is tolyl. The bond tothe parent moiety is through the aryl.

“Cycloalkylether” means a non-aromatic ring of 3 to 7 members comprisingan oxygen atom and 2 to 7 carbon atoms. Ring carbon atoms can besubstituted, provided that substituents adjacent to the ring oxygen donot include halo or substituents joined to the ring through an oxygen,nitrogen or sulfur atom.

“Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl,adamantylpropyl, and the like.

“Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable cycloalkenylalkyls include cyclopentenylmethyl,cyclohexenylmethyl and the like.

“Heteroarylalkyl” means a heteroaryl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl andthe like.

“Heterocyclylalkyl” (or “heterocycloalkylalkyl”) means a heterocyclylmoiety as defined above linked via an alkyl moiety (defined above) to aparent core. Non-limiting examples of suitable heterocyclylalkylsinclude piperidinylmethyl, piperazinylmethyl and the like.

“Heterocyclenylalkyl” means a heterocyclenyl moiety as defined abovelinked via an alkyl moiety (defined above) to a parent core.

“Alkynylalkyl” means an alkynyl-alkyl-group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl-group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Cyanoalkyl” means a NC-alkyl-group in which alkyl is as previouslydefined.

Preferred cyanoalkyls contain lower alkyl. Non-limiting examples ofsuitable cyanoalkyl groups include cyanomethyl and 2-cyanoethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described. The bond to the parentmoiety is through the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Heteroaroyl” means an heteroaryl-C(O)— group in which the heteroarylgroup is as previously described. The bond to the parent moiety isthrough the carbonyl. Non-limiting examples of suitable groups includepyridoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Alkyoxyalkyl” means a group derived from an alkoxy and alkyl as definedherein. The bond to the parent moiety is through the alkyl.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” (or “arylalkyloxy”) means an aralkyl-O— group (anarylaklyl-O— group) in which the aralkyl group is as previouslydescribed. Non-limiting examples of suitable aralkyloxy groups includebenzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moietyis through the ether oxygen.

“Arylalkenyl” means a group derived from an aryl and alkenyl as definedherein. Preferred arylalkenyls are those wherein aryl is phenyl and thealkenyl consists of about 3 to about 6 atoms. The arylalkenyl can beoptionally substituted by one or more substituents. The bond to theparent moiety is through a non-aromatic carbon atom.

“Arylalkynyl” means a group derived from a aryl and alkenyl as definedherein. Preferred arylalkynyls are those wherein aryl is phenyl and thealkynyl consists of about 3 to about 6 atoms. The arylalkynyl can beoptionally substituted by one or more substituents. The bond to theparent moiety is through a non-aromatic carbon atom.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

“Spirocycloalkyl” means a cycloalkyl group attached to a parent moietyat a single carbon atom. Non-limiting examples of spirocycloalkylwherein the parent moiety is a cycloalkyl include Spiro [2.5] octane,Spiro [2.4] heptane, etc. Non-limiting examples of spirocycloalkylwherein the parent moiety is an The alkyl moiety linking fused ringsystems (such as the alkyl moiety in heteroarylfused heteroarylalkyl-)may optionally be substituted with spirocycloalkyl or other groups asdescribed herein. Non-limiting spirocycloalkyl groups includespirocyclopropyl, spriorcyclobutyl, spirocycloheptyl, andspirocyclohexyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound” or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,heteroarylalkyl, arylfused cycloalkylalkyl-moiety or the like includessubstitution on any ring portion and/or on the alkyl portion of thegroup.

When a variable appears more than once in a group, e.g., R⁸ in —N(R⁸)₂,or a variable appears more than once in a structure presented hereinsuch as Formula (I), the variables can be the same or different.

With reference to the number of moieties (e.g., substituents, groups orrings) in a compound, unless otherwise defined, the phrases “one ormore” and “at least one” mean that there can be as many moieties aschemically permitted, and the determination of the maximum number ofsuch moieties is well within the knowledge of those skilled in the art.With respect to the compositions and methods comprising the use of “atleast one compound of the invention, e.g., of Formula (I),” one to threecompounds of the invention, e.g., of Formula (I) can be administered atthe same time, preferably one.

Compounds of the invention may contain one or more rings having one ormore ring system substituents. “Ring system substituent” means asubstituent attached to an aromatic or non-aromatic ring system which,for example, replaces an available hydrogen on the ring system. Ringsystem substituents may be the same or different, each being asdescribed herein or independently selected from the group consisting ofalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl,aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl,alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl,aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, —C(═N—CN)—NH₂, —C(═NH)—NH₂, —C(═NH)—NH(alkyl),Y₁Y₂N-alkyl-, Y₁Y₂NC(O)—, Y₁Y₂NSO₂— and —SO₂NY₁Y₂, wherein Y₁ and Y₂ canbe the same or different and are independently selected from the groupconsisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. “Ringsystem substituent” may also mean a single moiety which simultaneouslyreplaces two available hydrogens on two adjacent carbon atoms (one H oneach carbon) on a ring system. Examples of such moieties are rings suchas heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, andheterocycloalkenyl rings. Additional non-limiting examples includemethylene dioxy, ethylenedioxy, —C(CH₃)₂— and the like which formmoieties such as, for example:

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The line ----, as a bond generally indicates a mixture of, or either of,the possible isomers, e.g., containing (R)- and (S)-stereochemistry. Forexample:

means containing both

The wavy line , as used herein, indicates a point of attachment to therest of the compound. For example, each wavy line in the followingstructure:

indicates a point of attachment to the core structure, as describedherein.

Lines drawn into the ring systems, such as, for example:

-   -   indicate that the indicated line (bond) may be attached to any        of the substitutable ring carbon atoms.

“Oxo” is defined as a oxygen atom that is double bonded to a ring carbonin a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or otherring described herein, e.g.,

In this specification, where there are multiple oxygen and/or sulfuratoms in a ring system, there cannot be any adjacent oxygen and/orsulfur present in said ring system.

It is noted that the carbon atoms for compounds of the invention may bereplaced with 1 to 3 silicon atoms so long as all valency requirementsare satisfied.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

represents

The term “purified”, “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process (e.g. from a reaction mixture),or natural source or combination thereof. Thus, the term “purified”, “inpurified form” or “in isolated and purified form” for a compound refersto the physical state of said compound after being obtained from apurification process or processes described herein or well known to theskilled artisan (e.g., chromatography, recrystallization and the like),in sufficient purity to be characterizable by standard analyticaltechniques described herein or well known to the skilled artisan.

It should also be noted that any carbon (or other atom or heteroatom)with unsatisfied valences in the text, schemes, examples and Tablesherein is assumed to have the sufficient number of hydrogen atom(s) tosatisfy the valences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in Organic Synthesis(1991), Wiley, New York.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g, a drugprecursor) that is transformed in vivo to yield a compound of theinvention or a pharmaceutically acceptable salt, hydrate or solvate ofthe compound. The transformation may occur by various mechanisms (e.g.,by metabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and NV Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a compound of the invention or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₁)alkylamino(C₂-C₃)alkyl (such as (3-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di (C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of the invention contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of the invention incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄)alkyl and Y³ is (C₁-C₆)alkyl,carboxy (C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N- ordi-N,N-(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N- or di-N,N-(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of Solvates is Generally Known. Thus, for Example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient tofoini crystals which are then isolated by standard methods. Analyticaltechniques such as, for example IR spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the above-noted diseases and thus producing thedesired therapeutic, ameliorative, inhibitory or preventative effect.

The compounds of the invention can form salts which are also within thescope of this invention. Reference to a compound of the invention hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof the invention contains both a basic moiety, such as, but not limitedto a pyridine or imidazole, and an acidic moiety, such as, but notlimited to a carboxylic acid, zwitterions (“inner salts”) may be formedand are included within the term “salt(s)” as used herein.Pharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salts are preferred, although other salts are also useful.Salts of the compounds of the invention may be formed, for example, byreacting a compound of the invention with an amount of acid or base,such as an equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic phaimaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, acetyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di (C₆₋₂₄)acyl glycerol.

Compounds of the invention, and salts, solvates, esters and prodrugsthereof, may exist in their tautomeric form (for example, as an amide orimino ether). All such tautomeric forms are contemplated herein as partof the present invention.

The compounds of the invention may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of the invention as wellas mixtures thereof, including racemic mixtures, form part of thepresent invention. In addition, the present invention embraces allgeometric and positional isomers. For example, if a compound of theinvention incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of the invention may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of the invention may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of the invention incorporates a double bond or a fusedring, both the cis- and trans-forms, as well as mixtures, are embracedwithin the scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.).

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled compounds of the invention (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of the invention cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

Polymorphic forms of the compounds of the invention, and of the salts,solvates, esters and prodrugs of the compounds of the invention, areintended to be included in the present invention.

Suitable doses for administering compounds of the invention to patientsmay readily be determined by those skilled in the art, e.g., by anattending physician, pharmacist, or other skilled worker, and may varyaccording to patient health, age, weight, frequency of administration,use with other active ingredients, and/or indication for which thecompounds are administered. Doses may range from about 0.001 to 500mg/kg of body weight/day of the compound of the invention. In oneembodiment, the dosage is from about 0.01 to about 25 mg/kg of bodyweight/day of a compound of the invention, or a pharmaceuticallyacceptable salt or solvate of said compound. In another embodiment, thequantity of active compound in a unit dose of preparation may be variedor adjusted from about 1 mg to about 100 mg, preferably from about 1 mgto about 50 mg, more preferably from about 1 mg to about 25 mg,according to the particular application. In another embodiment, atypical recommended daily dosage regimen for oral administration canrange from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to200 mg/day, in two to four divided doses.

As discussed above, the amount and frequency of administration of thecompounds of the invention and/or the pharmaceutically acceptable saltsthereof will be regulated according to the judgment of the attendingclinician considering such factors as age, condition and size of thepatient as well as severity of the symptoms being treated.

When used in combination with one or more additional therapeutic agents,the compounds of this invention may be administered together orsequentially. When administered sequentially, compounds of the inventionmay be administered before or after the one or more additionaltherapeutic agents, as determined by those skilled in the art or patientpreference.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically active agent or treatment within its dosagerange.

Accordingly, in an aspect, this invention includes combinationscomprising an amount of at least one compound of the invention, or apharmaceutically acceptable salt, solvate, ester or prodrug thereof, andan effective amount of one or more additional agents described above.

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. Certain assays areexemplified elsewhere in this document.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered subcutaneously.

In one embodiment, the compound is administered orally.

In some embodiments, it may be advantageous for the pharmaceuticalpreparation comprising one or more compounds of the invention beprepared in a unit dosage form. In such forms, the preparation issubdivided into suitably sized unit doses containing appropriatequantities of the active component, e.g., an effective amount to achievethe desired purpose.

PREPARATIVE EXAMPLES

Compounds of the invention can be made using procedures known in theart. The following reaction schemes show typical procedures, but thoseskilled in the art will recognize that other procedures can also besuitable.

Techniques, solvents and reagents may be referred to by their followingabbreviations:

Thin layer chromatography: TLCHigh performance liquid chromatography: HPLCethyl acetate: AcOEt or EtOAcmethanol: MeOHether: Et₂Otetrahydrofuran: THF

Acetonitrile: MeCN

1,2-dimethoxyethane: DMETrifluoroacetic acid: TFA

Dimethylacetamide: DMA Dimethylformamide: DMF Dimethylsulfoxide: DMSO

triethylamine: Et₃N or TEAtert-Butoxycarbonyl: t-Boc or Boc

2-(Trimethylsilypethoxycarbonyl: Teoc

nuclear magnetic resonance spectroscopy: NMRliquid chromatography mass spectrometry: LCMShigh resolution mass spectrometry: HRMSmilliliters: mLmillimoles: mmolmicroliters: μlgrams: gmilligrams: mgcentimeters: cmroom temperature (ambient, about 25° C.): rtRetention time: tR

N-bromosuccinimide: NBS N-chlorosuccinimide: NCS

Methyl magnesium bromide: MeMgBriron(III) acetylacetonate: Fe(acac)₃Diphenylphosphoryl azide: DPPA1-(3-Dime(hylaminopropyl)-3-ethylcarbodiimide hydrochloride: EDCIDiisopropylethylamine: DIEA or i-Pr₂NEt or DIPEADiisopropylamine: i-Pr₂NH

2-(Trimethylsilyl)ethanol: TMSethanol

3-Chloroperoxybenzoic acid: mCPBAn-Butyllithium: nBuLilithium diisopropylamide: LDA[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II): PdCl₂dppfPalladium(II) acetate: Pd(OAc)₂Methanesulfonyl chloride: MeSO₂ClTriphenyl phosphine: TPP or Ph₃P

General Method

-   -   wherein X, Y, Z, R, R¹, R², R³ to R⁹, R¹⁸, R¹⁹, R²³, R²², and n        are as defined herein.

Step 1: The appropriately substituted benzyl triphenylphosphonium halide(e.g., 4-chlorobenzyltriphenylphosphonium chloride, 0.66 g, 1.56 mmol),was suspended in anhydrous THF (5.0 mL) with stirring under argon andcooled to −78° C. Then, nBuLi (0.6 mL, 2.5 M in hexane) was addeddropwise over 20 minutes and stirring was continued for an additional0.5 h. Compound 1 (0.2 g, 1.04 mmol) was suspended/partially dissolvedin anhydrous THF (15.0 mL) and added dropwise to the ylide solution. Thecooling bath was removed and the mixture was stirred at room temperaturefor 2 h whereby TLC (1:20 THF-CH₂Cl₂) showed no remaining startingmaterial, 1. The yellow solution was cooled to −78° C. and treatedcautiously with ammonium chloride (satd, 15 mL). The mixture removedfrom the cooling bath, and stirring was continued for 1.5 h before EtOAc(10.0 mL) was added. The organic phase was separated, washed with water(1×10 mL), dried (Na₂SO₄), filtered, and concentrated to dryness. Flashchromatography (1:20 THF-CH₂Cl₂) provided compound 2a (0.118 g, 37.7%,mixture of cis and trans isomers) as an off-white solid.

An alternative and more convenient workup and purification involvesconcentrating the crude reaction mixture to dryness and triturating thethusly obtained mass with chloroform (˜1 mL/mmol). The product was thenisolated by filtration, followed by washing the resulting product withchloroform (˜5 mL). After further drying in vacuo, this product can beused without further purification.

Compound 2

(Wittig reagent from 4-chlorobenzylchloride)

2a (˜1:9 cis/trans by NMR) ¹H NMR (DMSO-d₆): δ 6.36 (d, 1H, J=11.9 Hz,CH═CH_(cis)), 6.79 (d, 1H, CH═CH_(cis))_(,) 6.97 (d, 1H, J=16.6 Hz,CH═CH_(trans)), 7.06 (d, 1H, CH═CH_(trans)), 7.14 (d, 2H, J=8.6 Hz,Ar_(cis)), 7.37 (d, 2H, J=8.6 Hz, Ar_(cis)), 7.44 (d, 2H, J=8.5 Hz,Ar_(trans))_(,) 7.59-7.68 (m, 4H, Ar+NH₂).

2b (Wittig reagent from 2-chlorobenzylchloride)

2b ¹H NMR (DMSO-d₆): δ7.02 (d, 1H, J=16.5 Hz, CH═CH), 7.32-7.58 (m, 4H,Ar and CH═CH), 7.70 (s, 2H, NH₂), 7.83 (dd, 1H, J=1.8, 7.5 Hz, Ar).

2c (Wittig reagent from 2-fluorobenzylchloride)

2c ¹H NMR (DMSO-d₆): δ6.48 (d, 1H, J=11.8 Hz, CH═CH), 6.86 (d, 1H,CH═CH), 7.00-7.38 (m, 3H, Ar), 7.52-7.78 (m, 3H, Ar+NH₂).

Step 2:Compounds of type 3 were prepared following knownprocedures.^(1,2)

REFERENCES

-   (1) Vince, R.; Rua, M. Synthesis and anti-HIV activity of    carbocyclic 2′,3′-didehydro-2′,3′-dideoxy 2,6-disubstituted purine    nucleosides. J. Med. Chem. 1990, 33, 17-21.-   (2) Peterson, M. L.; Vince, R. Synthesis and biological evaluation    of carbocyclic analogues of lyxofuranosides of    2-amino-6-substituted-purines and    2-amino-6-substituted-8-azapurines. J. Med. Chem. 1990, 33,    1214-1219.

In other embodiments, the compounds of the invention have a structuralformula as depicted in Table I below and include tautomers, andpharmaceutically acceptable salts, esters, prodrugs, isomers, andsolvates of such compounds and such tautomers.

TABLE I Compd # Structure EC90 (uM) 1H NMR data MS 1

A (DMSO-d₆, mixture of cis and trans isomers): δ 11.02-1.12 (m, 1H),1.81-1.93 (m, 1H), 2.08- 2021 (m, 1H), 3.2-3.45 (m, 2H), 3.68-3.82 (m,2H), 3.72 (s, 3H), 3.81 (s, 3H), 4.24-4.38 (m, 1H), 4.37 (d, 1H, J = 4.5Hz), 4.60-4.69 (m, 2H), 6.06 and 6.67 (d, 1H, J = 11.4 and 16.5 Hz),6.40-6.55 (m, 2H, J = 6.60 and 18.6 Hz), 6.94 (d, 1H, J = 8.5 Hz), 7.04(d, 1H. J = 1.7, 8.4 Hz), 7.15 (br d, 1H, J = 1.5 Hz), 9.95-10.23 (br s,1H). 437.2 (Cl pattern) 2

A (DMSO-d₆): δ 1.14 (m, 1H), 1.89 (m, 1H), 2.15 (m, 1H), 3.77 (m, 2H),4.34 (d, 2H, J = 5.3 Hz), 4.60 (m, 2H), 6.55 (s, 2H, NH₂), 6.60 (d, 1H,J = 7.8 Hz, Ar), 6.88 (m, 2H), 7.09 (m, 1H), 7.32-7.46 (m, 3H, Ar).395.2 (Cl pattern) 3

A (CD₃OD):

 1.30 (dt, 1H, J = 7.8, 13.4 Hz), 2.11 (m, 1H), 2.29 (m, 1H), 3.57 (d,2H, J = 5.3 Hz), 3.89 (m, 2H), 4.40 (m, 1H), 6.85 (d, 1H, J = 16.5 Hz),7.30 (d, 1H, J = 16.5 Hz), 7.22-7.41 (m, 3H, Ar), 7.76 (d, 1H, J = 7.7Hz, Ar); 411.3 (Cl pattern) 4

A (DMSO-d₆):

 1.09 (dt, 1H, J = 8.6, 13.1 Hz), 1.81-1.94 (m 1H), 2.08- 2.21 (m, 1H),3.28-3.43 (m, 2H), 3.68-3.74 (m, 1H), 3.75-3.81 (m, 1H), 4.28-4.40 (m,1H), 4.59 (d, 1H, J = 5.4 Hz),4.63 (t, 1H, J = 5.1 Hz), 6.53- 6.68 (m,2H), 6.86 (d, 1H, J = 16.5 Hz, app d at 6.1 for corr H in isomer), 6.97(d, 1H, J = 16.4 Hz; d at 6.32, J = 11.7 Hz for corr H in isomer), 7.1(ttt, 1H, J = 11.5, 2.3, 4.6 Hz), 7.24-7.33 (m, 2H). 413.1 5

A (DMSO-d6):

 1.09 (dt, 1H, J = 8.4, 13.2 Hz), 1.80-1.94 (m 1H), 2.08- 2.20 (m, 1H),3.30-3.42 (m, 2H + H₂O), 3.68- 3.75 (m, 1H), 3.74-3.82 (m, 1H), 3.79 (s,3H), 4.27-4.40 (m, 2H), 4.58- 4.67 (m, 2H), 6.48-6.60 (m, 2H), 6.83 (s,2H), 6.82-6.88 (m, 1H), 7.08- 7.15 (m, 2H), 7.28 (t, 1H, J = 7.9 Hz).407.2 (Cl pattern) 6

A (DMSO-d₆):

 1.09 (dt, 1H, J = 8.3, 12.9 Hz), 1.81-1.95 (m 1H), 2.08- 2.21 (m, 1H),3.28-3.43 (m, 2H), 3.68-3.75 (m, 1H), 3.75-3.81 (m, 1H), 4.28-4.40 (m,1H), 4.59 (d, 1H, J = 5.3 Hz), 4.64 (t, 1H, J = 5.1 Hz), 6.60- 6.73 (m,2H), 6.84 (s, 2H), 7.32-7.48 (m, 2H), 6.62-6.72 (m, 1H). 413.2 7

A (DMSO-d₆): δ 1.14 (m, 1H), 1.89 (m, 1H), 2.15 (m, 1H), 3.77 (m, 2H),4.34 (d, 2H, J = 5.3 Hz), 4.60 (m, 2H), 6.57 (s, 2H, NH₂), 6.67 (d, 1H,J = 7.8 Hz, Ar), 7.22- 7.41 (m, 3H, Ar), 7.76 (dt, 1H, J = 6.3, 7.6 Hz,Ar). 395.2 8

A (CD₃OD, mixture of cis and trans isomers):

 0.91-1.02 and 1.28- 1.41 (m, 1H), 1.97-2.09 and 2.08-2.18 (m, 1H),2.17-2.24 and 2.37-2.49 (m, 1H), 3.51 and 3.58 (d, 2H, J = 5.3 Hz),3.53- 3.71 and 3.88-3.97 (m, 2H); 4.13-4.22 and 4.38- 4.47 (m, 1H),6.52, 6.95, 7.14, 7.27 (d, 2H, J = 11.6, 11.6, 6.5, 6.5 Hz, resp.),7.35-7.75 (m, 4H, Ar), 7.91 (d, 1H, J = 8.1 Hz, NH₂). 402.2 (1 Clpattern) 9

A (DMSO-d₆):

 1.09 (dt, 1H, J = 8.5, 13.1 Hz), 2.08-2.20 (m 1H), 3.30- 3.42 (m, 2H),3.68-3.74 (m, 1H; 3.48-3.57 m for corr H in isomer), 3.73- 3.82 (m, 1H;3.54-3.62 m for corr H in isomer), 4.32-4.42 (m, 2H), 4.57 (d, 1H, J =5.4 Hz; multiplet at 4.11-4.22 for corr H in isomer), 4.62 (t, 1H, J =5.1 Hz; multiplet at 4.30-4.33 for corr H in isomer), 6.98 (s, 2H;doublets at 6.07, J = 7.3 Hz and 6.43, J = 11.8 Hz for corr Hs inisomer), 6.62 (br s, 1H: br s at 6.49 for corr H in isomer); 7.18-7.40(m, 2H; m at 6.90-7.13 for corr Hs in isomer), 7.65-7.75 (m, 1H). 413.210

A (DMSO-d₆):

 1.02-1.15 (m, 1H), 1.80-1.93 (m 1H), 2.08-2.20 (m, 1H), 3.17 (d, 1H, J= 5.2 Hz), 3.32-3.45 (m, 1H), 3.67- 3.82 (m, 2H), 4.08-4.15 (m, 1H),4.28-4.40 (m 2H, D₂O exchangeable), 4.58-4.68 (m 2H, D₂O exchangeable),6.54 (br s, 2H), 6.59 (d, 1H, J = 7.6 Hz), 6.86 (br s, 2H), 6.86-6.93(m, 1H), 7.01 (s, 1H), 7.04 (s, 1H), 7.14 (app t, 1H, J = 7.4 Hz), 7.24(br s, 1H), 7.29-7.46 (m, 4H). 469.2 (Cl pattern) 11

A (DMSO-d₆):

 1.05-1.17 (m, 1H), 1.82-1.94 (m 1H), 2.09-2.21 (m, 1H), 3.49-3.66 (m,2H), 3.68- 3.79 (m, 2H), 4.10-4.90 (m, 4H), 6.49-6.63 (m, 1H), 6.65-6.71(m, 1H), 6.89 (d, 1H, J = 6.5 Hz), 6.99 (d, 1H, J = 6.5 Hz), 7.38-7.50(m, 1H), 8.0- 8.08 (m, 1H), 8.40-8.50 (m, 1H), 8.70-8.74 (m, 1H). 378.1(Cl pattern) 12

B (CD₃OD):

 1.28-1.34 (m, 1H), 2.04-2.14 (m, 1H), 2.33 (s, 3H), 2.28- 2.44 (m, 1H),3.57 (d, 2H, J = 5.1 Hz), 3.85 (app t, 1H, J = 5.6 Hz), 3.91 (app t, 1H,J = 5.2 Hz), 4.03-4.42 (m, 1H), 6.80 (d, 1H, J = 16.6 Hz), 6.83 (d, 1H,J = 6.7 Hz), 7.16 (d, 1H, J = 8.0 Hz), 7.39 (d, 1H, J = 8.1 Hz). 391.2(Cl pattern) 13

B (DMSO-d₆, mixture of cis and trans isomers):

 0.94-1.02 and 1.01- 1.13 (m, 1H), 1.70-1.86 and 1.80-1.93 (m, 1H),2.08-2.20 (m, 1H), 2.23 and 2.33 (s, 3H), 32.0- 3.30 and 3.51-3.60 (m,2H), 3.67-3.73 (m, 1H), 3.73-3.81 (m, 1H), 4.28- 4.40 (m, 2H), 4.57-4.68(m, 2H), 6.28, 6.72 (d, 1H, J = 11.6 and 16.4 Hz, respectively), 6.39and 6.52 (br s, 1H, NH₂), 6.61 (d, 1H, J = 7.8 Hz, NH), 7.09 (d, 1H, J =16.4 Hz), 7.15- 7.28 (m, 3H, Ar), 7.66 (d, 1H, J = 7.0 Hz). 391.2 (Clpattern) 14

B (DMSO-d₆):

 1.09 (dt, 1H, J = 8.2, 13.0 Hz), 1.81-1.93 (m 1H), 2.08- 2.20 (m, 1H),3.31 (m, 2H), 3.68-3.80 (m, 2H), 3.77 (s, 3H), 4.27-4.39 (m, 2H),4.58-4.66 (m, 2H), 6.42-6.53 (m, 2H), 6.67 (d, 1H, J = 16.6 Hz), 6.78(d, 1H, J = 16.5 Hz), 6.93 (app d, 2H, J = 8.8 Hz), 7.47 (app d, 2H, J =8.8 Hz). 407.2 (Cl pattern) 15

C (DMSO-d₆): δ 1.24 (m, 1H), 1.79 (m, 3H), 2.15 (m, 1H, m), 3.77 (d, 3H,J = 5.3 Hz), 3.40 (m, 1H), 3.91 (m, 1H), 4.11 (m, 1H), 4.61 (m, 3H),6.55 (s, 2H, NH₂), 6.63 (d, 1H, J = 7.8 Hz), 6.93 (d, 2H, J = 16.6 Hz),7.22- 7.36 (m, 3H, Ar), 7.76 (dt, 1H, J = 6.3, 7.6 Hz, Ar). 379.2 16

C (DMSO-d₆; mixture of cis and trans isomers):

 0.82-0.95 and 1.20- 1.37 (m, 1H), 2.05-2.18 and 2.30-2.42 (m, 1H),2.05-2.20 (m, 1H), 2.43, 2.44 (s, 3H), 3.35-3.42 (m, 2H), 3.56 (m, 1H),3.79-3.93 (m, 1H), 3.94- 4.02 and 4.27-4.36 (m, 1H), 6.19-6.22 and 6.60-6.87 (m, 2H), 7.08-7.57 (m, 5H). 389.2 17

B (DMSO-d₆):

 1.34-1.42 (app dt, 1H, J = 5.9 Hz), 2.39 (dt, 1H, J = 8.0, 13.0 Hz),2.66-2.78 (m 1H), 3.38 (t, 2H, J = 5.5 Hz), 4.68 (t, 1H, J = 5.1 Hz),5.11-5.22 (m, 1H), 5.77-5.82 (m, 1H), 5.83- 5.89 (m, 1H), 6.62 (br s,2H, NH₂), 6.74 (d, 1H, J = 7.8 Hz), 6.88 (d, 1H, J = 16.4 Hz), 7.19 (d,1H, J = 16.4 Hz), 7.25-7.32 (m, 1H), 7.33-7.39 (m, 1H), 7.45 (dd, 1H, J= 1.3, 7.8 Hz), 7.83 (dd, 1H, J = 7.8, 1.6 Hz). 377.2 (2 Cl pattern)

Assays Cell-Based HCV Replicon Assay

To measure cell-based anti-HCV activity of the compounds of the presentinvention, replicon cells were seeded at 5000 cells/well in 96-wellcollagen I-coated Nunc plates in the presence of the compound of theinvention. Various concentrations of a compound of the invention,typically in 10 serial 2-fold dilutions, were added to the assaymixture, the starting concentration of the compound ranging from 25 μMto 1 μM. The final concentration of DMSO was 0.5%, fetal bovine serumwas 10%, in the assay media. Cells were harvested on day 3 by theaddition of 1× cell lysis buffer (Ambion cat #8721). The replicon RNAlevel was measured using real time PCR (Taqman assay). The amplicon waslocated in 5B. The PCR primers were: 5B.2F, ATGGACAGGCGCCCTGA; 5B.2R,TTGATGGGCAGCTTGGTTTC; the probe sequence was FAM-labeledCACGCCATGCGCTGCGG. GAPDH RNA was used as endogenous control and wasamplified in the same reaction as NS5B (multiplex PCR) using primers andVIC-labeled probe recommended by the manufacturer (PE AppliedBiosystem). The real-time RT-PCR reactions were run on ABI PRISM 7900HTSequence Detection System using the following program: 48° C. for 30min, 95° C. for 10 min, 40 cycles of 95° C. for 15 sec, 60° C. for 1min. The ΔCT values (CT_(5B)-CT_(GAPDH)) were plotted against theconcentration of test compound and fitted to the sigmoid dose-responsemodel using GraphPad PRISM software. EC₅₀ was defined as theconcentration of inhibitor necessary to achieve ΔCT=1 over the projectedbaseline; EC₉₀ the concentration necessary to achieve ΔCT=3.2 over thebaseline. Alternatively, to quantitate the absolute amount of repliconRNA, a standard curve was established by including serially diluted T7transcripts of replicon RNA in the Taqman assay. All Taqman reagentswere from PE Applied Biosystems. Such an assay procedure was describedin detail in e.g. Malcolm et al., Antimicrobial Agents and Chemotherapy50: 1013-1020 (2006).

HCV Replicon assay data for compounds of the invention that were testedwas obtained using the above method. Calculated EC₉₀ values are reportedfor each compound in Table I as a falling within the following ranges:

“A”—less than or equal to about 5 μM

“B”—greater than about 5 μM

“**” indicates that the value was not available for the compound

Methods of Use

The compounds of the invention are useful in human and veterinarymedicine for treating or preventing a viral infection or a virus-relateddisorder in a patient. In accordance with the invention, the compoundsof the invention can be administered to a patient in need of treatmentor prevention of a viral infection or a virus-related disorder.

Accordingly, in one embodiment, the invention provides methods fortreating a viral infection in a patient comprising administering to thepatient an effective amount of at least one compounds of the inventionor a pharmaceutically acceptable salt, ester, prodrug, isomer, tautomer,or solvate thereof. In another embodiment, the invention providesmethods for treating a virus-related disorder in a patient comprisingadministering to the patient an effective amount of at least onecompounds of the invention or a pharmaceutically acceptable salt, ester,prodrug, isomer, tautomer, or solvate thereof.

Treatment or Prevention of a Viral Infection

The compounds of the invention can be used to treat or prevent a viralinfection. In one embodiment, the compounds of the invention can be usedto inhibit viral replication. In a specific embodiment, the compounds ofthe invention can be inhibitors of HCV replication. Accordingly, thecompounds of the invention are useful for treating viral diseases anddisorders related to the activity of a virus, such as HCV polymerase.

Such uses as are described herein may be performed in a patient in needthereof, although in vitro and ex vivo uses, such as in diagnostic andresearch contexts, are also contemplated. References made herein to theuse of compounds of the invention also refers to uses of compositionscomprising compounds of the invention.

Examples of viral infections that can be treated or prevented using thepresent methods, include but are not limited to, hepatitis A infection,hepatitis B infection and hepatitis C infection.

In one embodiment, the viral infection is hepatitis C infection.

In one embodiment, the hepatitis C infection is acute hepatitis C. Inanother embodiment, the hepatitis C infection is chronic hepatitis C.

The compositions and combinations of the present invention can be usefulfor treating a patient suffering from infection related to any HCVgenotype. HCV types and subtypes may differ in their antigenicity, levelof viremia, severity of disease produced, and response to interferontherapy as described in Holland et al., Pathology, 30(2):192-195 (1998).The nomenclature set forth in Simmonds et al., J Gen Virol, 74(Pt11):2391-2399 (1993) is widely used and classifies isolates into sixmajor genotypes, 1 through 6, with two or more related subtypes, e.g.,1a, 1b. Additional genotypes 7-10 and 11 have been proposed, however thephylogenetic basis on which this classification is based has beenquestioned, and thus types 7, 8, 9 and 11 isolates have been reassignedas type 6, and type 10 isolates as type 3 (see Lamballerie et al, J GenViral, 78(Pt1):45-51 (1997)). The major genotypes have been defined ashaving sequence similarities of between 55 and 72% (mean 64.5%), andsubtypes within types as having 75%-86% similarity (mean 80%) whensequenced in the NS-5 region (see Simmonds et al., J Gen Viral, 75(Pt5):1053-1061 (1994)).

Treatment or Prevention of a Virus-Related Disorder

The compounds of the invention can be used to treat or prevent avirus-related disorder. Accordingly, the compounds of the invention areuseful for treating disorders related to the activity of a virus, suchas liver inflammation or cirrhosis. Virus-related disorders include, butare not limited to, RNA-dependent polymerase-related disorders anddisorders related to HCV infection.

Treatment or Prevention of a RNA-Dependent Polymerase-Related Disorder

The compounds of the invention are useful for treating or preventing aRNA dependent polymerase (RdRp) related disorder in a patient. Suchdisorders include viral infections wherein the infective virus contain aRdRp enzyme.

Accordingly, in one embodiment, the present invention provides a methodfor treating a RNA dependent polymerase-related disorder in a patient,comprising administering to the patient an effective amount of at leastone compounds of the invention or a pharmaceutically acceptable salt,solvate, ester or prodrug thereof.

Treatment or Prevention of a Disorder Related to HCV Infection

The compounds of the invention can also be useful for treating orpreventing a disorder related to an HCV infection. Examples of suchdisorders include, but are not limited to, cirrhosis, portalhypertension, ascites, bone pain, varices, jaundice, hepaticencephalopathy, thyroiditis, porphyria cutanea tarda, cryoglobulinemia,glomerulonephritis, sicca syndrome, thrombocytopenia, lichen planus anddiabetes mellitus.

Accordingly, in one embodiment, the invention provides methods fortreating an HCV-related disorder in a patient, wherein the methodcomprises administering to the patient a therapeutically effectiveamount of at least one compound of the invention, or a pharmaceuticallyacceptable salt, solvate, ester or prodrug thereof.

Combination Therapy

In another embodiment, the present methods for treating or preventing aviral infection can further comprise the administration of one or moreadditional therapeutic agents. In one embodiment, such one or moreadditional therapeutic agent may be one or more additional compounds ofthe invention. In another embodiment, such one or more additionaltherapeutic agent is an agent other than a compound of the invention.

In one embodiment, the additional therapeutic agent is an antiviralagent. Non-limiting examples of antiviral agents are as described hereinand include, e.g., interferon.

In another embodiment, the additional therapeutic agent is animmunomodulatory agent, such as an immunosuppressive agent.

Accordingly, in one embodiment, the present invention provides methodsfor treating a viral infection in a patient, the method comprisingadministering to the patient: (i) at least one compound of theinvention, or a pharmaceutically acceptable salt, solvate, ester orprodrug thereof, and (ii) at least one antiviral agent other than acompound of the invention, wherein the amounts administered are togethereffective to treat or prevent a viral infection.

When administering such a combination to a patient, the therapeuticagents in the combination, or a pharmaceutical composition orcompositions comprising the therapeutic agents, may be administered inany order such as, for example, sequentially, concurrently, together,simultaneously and the like. The amounts of the various actives in suchcombination therapy may be different amounts (different dosage amounts)or same amounts (same dosage amounts). Thus, for non-limitingillustration purposes, a compound of the invention and an additionaltherapeutic agent may be present in fixed amounts (dosage amounts) in asingle dosage unit (e.g., a capsule, a tablet and the like). (Acommercial example of such single dosage unit containing fixed amountsof two different active compounds is VYTORIN (available from MerckSchering-Plough Pharmaceuticals, Kenilworth, N.J.)).

In one embodiment, the at least one compound of the invention isadministered at time when the additional antiviral agent(s) exert theirprophylactic or therapeutic effect, or vice versa.

In another embodiment, the at least one compound of the invention andthe additional antiviral agent(s) are administered in doses commonlyemployed when such agents are used as monotherapy for treating a viralinfection.

In another embodiment, the at least one compound of the invention andthe additional antiviral agent(s) are administered in doses lower thanthe doses commonly employed when such agents are used as monotherapy fortreating a viral infection.

In another embodiment, the at least one compound of the invention andthe additional antiviral agent(s) act synergistically and areadministered in doses lower than the doses commonly employed when suchagents are used as monotherapy for treating a viral infection.

In one embodiment, the at least one compound of the invention and theadditional antiviral agent(s) are present in the same composition. Inone embodiment, this composition is suitable for oral administration. Inanother embodiment, this composition is suitable for intravenousadministration.

Viral infections and virus-related disorders that can be treated orprevented using the combination therapy methods of the present inventioninclude, but are not limited to, those listed above.

In one embodiment, the viral infection is HCV infection.

The at least one compound of the invention and the additional antiviralagent(s) can act additively or synergistically. A synergisticcombination may allow the use of lower dosages of one or more agentsand/or less frequent administration of one or more agents of acombination therapy. A lower dosage or less frequent administration ofone or more agents may lower toxicity of the therapy without reducingthe efficacy of the therapy.

In one embodiment, the administration of at least one compound of theinvention and the additional antiviral agent(s) may inhibit theresistance of a viral infection to these agents.

Non-limiting examples of other therapeutic agents useful in the presentcompositions and methods include an an viral (e.g., HCV) polymeraseinhibitor, a viral (e.g., HCV) protease inhibitor, an interferon, aviral replication inhibitor, an antisense agent, a therapeutic vaccine,a viral protease inhibitor, a virion production inhibitor, animmunosuppressive agent, an antiviral antibody, a CYP-450 inhibitor, anantiviral booster, and an antiviral sensitizer, and any agent useful fortreating an RNA-dependent polymerase-related disorder.

In one embodiment, the at least one additional antiviral agent is aviral polymerase inhibitor.

In another embodiment, the at least one additional antiviral agent is anHCV polymerase inhibitor.

In one embodiment, the at least one additional antiviral agent is aviral protease inhibitor.

In another embodiment, the at least one additional antiviral agent is anHCV protease inhibitor.

In another embodiment, the at least one additional antiviral agent is aninterferon.

In still another embodiment, the at least one additional antiviral agentis a viral replication inhibitor.

In another embodiment, the at least one additional antiviral agent is anantisense agent.

In another embodiment, the at least one additional antiviral agent is atherapeutic vaccine.

In a further embodiment, the at least one additional antiviral agent isan virion production inhibitor.

In another embodiment, the at least one additional antiviral agent is anantibody.

In another embodiment, the at least one additional antiviral agentscomprise a protease inhibitor and a polymerase inhibitor.

In still another embodiment, the at least one additional antiviralagents comprise a protease inhibitor and an immunosuppressive agent.

In yet another embodiment, the at least one additional antiviral agentscomprise a polymerase inhibitor and an immunosuppressive agent.

In a further embodiment, the at least one additional antiviral agentscomprise a protease inhibitor, a polymerase inhibitor and animmunosuppressive agent.

In another embodiment the at least one additional agent is ribavirin,Levovirin, or Viramidine.

In other embodiments, pharmaceutical compositions according to theinvention comprise at least one compound of the invention and a CYP-450inhibitor. Non-limiting examples of suitable CYP-450 inhibitors includeritonavir.

In other embodiments, pharmaceutical compositions according to theinvention comprise at least one compound of the invention and aninterferon. Non-limiting examples of such interferon are as describedherein and include alpha interferon, pegylated interferon and conjugatesthereof. Additional non-limiting examples of interferon includePEG-intro™ m brand pegylated interferon, Pegasys™ brand pegylatedinterferon, Infergen™ brand interferon, and Alferon™ brand pegylatedinterferon.

In other embodiments, pharmaceutical compositions according to theinvention comprise at least one compound of the invention and aninterferon. Further comprising ribavirin, Levovirin, or Viramidine.

In other embodiments, pharmaceutical compositions according to theinvention comprise at least one compound of the invention and a proteaseinhibitor.

In other embodiments, pharmaceutical compositions according to theinvention comprise at least one compound of the invention, a proteaseinhibitor, and an interferon.

In other embodiments, pharmaceutical compositions according to theinvention comprise at least one compound of the invention, a proteaseinhibitor, an interferon, and ribavirin.

In other embodiments, pharmaceutical compositions according to theinvention comprise at least one compound of the invention, a polymeraseinhibitor, and an interferon.

In other embodiments, pharmaceutical compositions according to theinvention comprise at least one compound of the invention, a polymeraseinhibitor, an interferon, and ribavirin.

In other embodiments, pharmaceutical compositions according to theinvention comprise at least one compound of the invention, a proteaseinhibitor, polymerase inhibitor, and an interferon.

In other embodiments, pharmaceutical compositions according to theinvention comprise at least one compound of the invention, a proteaseinhibitor, a polymerase inhibitor, an interferon, and ribavirin.

HCV polymerase inhibitors useful in the present methods and compositionsinclude, but are not limited to VP-19744 (Wyeth/ViroPharma), HCV-796(Wyeth/ViroPharma), NM-283 (Idenix/Novartis), R-1626 (Roche), MK-0608(Merck), A848837 (Abbott), GSK-71 185 (Glaxo SmithKline), XTL-2125 (XTLBiopharmaceuticals), and those disclosed in Ni et al., Current Opinionin Drug Discovery and Development, 7(4):446 (2004); Tan et al., NatureReviews, 1:867 (2002); and Beaulieu et al., Current Opinion inInvestigational Drugs, 5:838 (2004).

Additional non-limiting examples of HCV polymerase inhibitors useful inthe present methods and compositions include: MK00608, NM283, HCV796,R1626, A848837, GSK71185, R7128, VCH759, GS9190, VP19744, and XTL2125.

Additional non-limiting examples of HCV polymerase inhibitors and HCVprotease inhibitors useful in the present methods and compositionsinclude: ANA598 (Anadys Pharmaceuticals), ABT-333, (Abbott), VCH-916,(Virochem), MK7009, (Merck), PF-00868554, (Pfizer) VX-500, (Vertex)GS9190, (Gilead) GSK625433, (GlazoSmithKline) ITMN-191 (R-7227),(Intermune), R7128, (Pharmasset/Roche), VCH-759 (Virochem), R1626,(Roche), TMC435350, (Medivir/Tibotec), SCH 503034 (Boceprevir),SCH900518 (Schering), and VX 950 (telaprevir) (Vertex). Additionalnon-limiting examples of HCV polymerase inhibitors include MK-3281(Merck), PSI-7851 (Pharmasset), IDX184 (Indenix), ANA598 (Anadys),ABT-333 (Abbott), VCH-916 (Vertex), PF-0086554 (Pfizer), R7128(Pharmasset/Roche), GS 9190 (Gilead), and VCH-759 (Vertex).

Additional non-limiting examples of agents useful in the present methodsand compositions include: SPC3649 (LNA-antimiR™-122), microRNA, SantarisPharma, CF102, (A3AR AGONISTS) (CAN-FITE), IMO-2125, TLR9 agonist,(Idera Pharmaceuticals), PYN17, Botanical, (Phynova), Bavituximab(formerly Tarvacin), Anti-Phospholipid Therapy , (Peregrine), A-831and/or A-832 (each of which are listed as NS5A Inhibitors fromArrowTherapeutics Ltd.), BMS-790052 (NS5A inhibitors from BMS), NOV-205,Immunomodulator, (Novelos Therapeutics), CTS-1027, Anti-inflammatory,(Conatus), Oglufanide disodium, Immunomodulator, (Implicit Bioscience),Alinia (nitazoxanide), Thiazolides , (Romark Laboratories), SCV-07,Broad spectrum immune stimulator, (SciClone), MitoQ (mitoquinone),Inflammation/Fibrosis Inhibitor, (Antipodean Pharmaceuticals),DEBIO-025, Cyclophilin inhibitor, (Debio Pharm Group), SCY-635,cyclophilin inhibitor (SCYNEXIS), PF-03491390 (Formerly IDN-6556),Pancaspase Inhibitor, (Pfizer Pharmaceuticals), Civacir, HCV ImmuneGlobulin, NABI, MX-3253 (celgosivir), Glucosidase I Inhibitor,(MIGENIX), VGX-410C (Mifepristone), IRES Inhibitor, (VGXPharmaceuticals), Viramidine (Taribavirin), Nucleoside Analogue,(Valeant Pharmaceuticals), and ZADAXINO (thymalfasin or thymosin alpha1), Immunomodulator, (SciClone/Sigma-Tau).

Additional non-limiting examples of agents useful in the present methodsand compositions include: TLR agonists (e.g., ANA773, AnadysPharmaceuticals), immunomodulators (e.g., CYT107, Cytheris; oglufanidedisodium, Implicit Bioscience), microRNA (e.g., SPC3649(LNA-antimiR™-122, Santaris Pharma), A3AR agonists (e.g., CF102,CAN-FITE), TLR⁹ agonists (e.g., Idera Pharmaceuticals),anti-phospholipid therapeutics (e.g., bavituximab (formerly Tarvacin),Peregrine), immunomodulators (e.g., NOV-205, Novelos Therapeutics),caspase inhibitors (e.g., GS-9450, Gilead), anti-inflammatories (e.g.,CTS-1027, Conatus), thiazolides (e.g., alinia (nitazoxanide), RomarkLaboratories), broad spectrim immune stimulators (e.g., SCV-07,SciClone), inflammation/fibrosis inhibitors (e.g., MitoQ (mitoquinone),Antipodean Pharmaceuticals, cyclophilin inhibitors (e.g., DEBIO-025,Debio Pharm Group), pancaspase inhibitors (e.g., PF-03491390 (formerlyIDN-6556, Pfizer Pharmaceuticals), and nucleoside analogues (e.g.,Viramidine (Taribavirin), Valeant Pharmaceuticals).

Interferons useful in the present methods and compositions include, butare not limited to, interferon alfa-2a, interferon alfa-2b, interferonalfacon-1 and PEG-interferon alpha conjugates. “PEG-interferon alphaconjugates” are interferon alpha molecules covalently attached to a PEGmolecule. Illustrative PEG-interferon alpha conjugates includeinterferon alpha-2a (Roferon™, Hoffman La-Roche, Nutley, N.J.) in theform of pegylated interferon alpha-2a (e.g., as sold under the tradename Pegasys™), interferon alpha-2b (Intron™, from Schering-PloughCorporation) in the form of pegylated interferon alpha-2b (e.g., as soldunder the trade name PEG-Intron™), interferon alpha-2c (Berofor Alpha™,Boehringer Ingelheim, Ingelheim, Germany), interferon alpha fusionpolypeptides, or consensus interferon as defined by determination of aconsensus sequence of naturally occurring interferon alphas (Infergen™,Amgen, Thousand Oaks, Calif.).

Additional examples of Interferons useful in the present methods andcompositions include, but are not limited to: IL-29 (PEG-InterferonLambda), Long acting Interferon, ZymoGenetics, Oral Interferon alpha,Oral Interferon, (Amarillo Biosciences), Belerofon (oral), Oralinterferon , (Nautilus Biotech), BLX-883 (Locteron), Long ActingInterferon, (Biolex Therapeutics/OctoPlus), Omega Interferon,Interferon, (Intarcia Therapeutics), Albuferon, Long Acting Interferon(injections every two weeks), (Human Genome Sciences), Consensusinterferon (Infergen), and Interferon, (Three Rivers Pharma).

Antiviral antibodies (antibody therapy agents) useful in the presentmethods and compositions include, but are not limited to, antibodiesspecific to IL-10 (such as those disclosed in US Patent Publication No.US2005/0101770, humanized 12G8, a humanized monoclonal antibody againsthuman IL-10, plasmids containing the nucleic acids encoding thehumanized 12G8 light and heavy chains were deposited with the AmericanType Culture Collection (ATCC) as deposit numbers PTA-5923 and PTA-5922,respectively), and the like). Viral protease inhibitors useful in thepresent methods and compositions include, but are not limited to, NS3serine protease inhibitors (including, but are not limited to, thosedisclosed in U.S. Pat. Nos. 7,012,066, 6,914,122, 6,911,428, 6,846,802,6,838,475, 6,800,434, 5,017,380, 4,933,443, 4,812,561 and 4,634,697; andU.S. Patent Publication Nos. US20020160962, US20050176648 andUS20050249702), HCV protease inhibitors (e.g., SCH503034(Schering-Plough), VX-950 (Vertex), GS-9132 (Gilead/Achillion), ITMN-191(InterMune/Roche)), and HIV protease inhibitors (e.g., amprenavir,atazanavir, fosemprenavir, indinavir, lopinavir, ritonavir, nelfinavir,saquinavir, tipranavir and TMC114).

Viral replication inhibitors useful in the present methods andcompositions include, but are not limited to, NS3 helicase inhibitors,NS5A inhibitors, ribavirin, viramidine, A-831 (Arrow Therapeutics); anantisense agent or a therapeutic vaccine.

In one embodiment, viral replication inhibitors useful in the presentmethods and compositions include, but are not limited to, NS3 helicaseinhibitors or NS5A inhibitors.

Examples of protease inhibitors useful in the present methods include,but are not limited to, an HCV protease inhibitor and a NS-3 serineprotease inhibitor.

Examples of NS-3 serine protease inhibitors include, but are not limitedto, SCH 503034 (Boceprevir), SCH900518 (Schering), Telaprevir (VX950),ITMN-191, TMC435350, GS9132, MK7009, and BILN2061.

Examples of HCV protease inhibitors useful in the present methodsinclude, but are not limited to, those disclosed in Landro et al.,Biochemistry, 36(31):9340-9348 (1997); Ingallinella et al.,Biochemistry, 37(25):8906-8914 (1998); Llinas-Brunet et al., Bioorg MedChem Lett, 8(13):1713-1718 (1998); Martin et al., Biochemistry,37(33):11459-11468 (1998); Dimasi et al., J Virol, 71(10):7461-7469(1997); Martin et al., Protein Eng, 10(5):607-614 (1997); Elzouki etal., J Hepat, 27(1):42-48 (1997); BioWorld Today, 9(217):4 (Nov. 10,1998); and International Publication Nos. WO 98/14181; WO 98/17679, WO98/17679, WO 98/22496 and WO 99/07734. Additional non-limiting examplesof protease inhibitors include ACH-1625 (Achillion), ABT-450(Abbott/Enanta), BI201335 (Boehringer Ingelheim Pharma), VX-813(Vertex), PHX1766 (Phenomix), VX-500 (Vertex), ITMN-191 (R-7227)(InterMune), MK7009 (Merck), BI 207127 (Boerhinger Ingelheim), SCH900518(Schering/Merck), TMC435 (Medivir/Tibotec), SCH 503034 (Boceprevir),SCH900518 (Schering), Telapravir (VX950) and (Vertex), XTL-2125 (XTLBiopharmaceuticals).

Additional examples of other therapeutic agents useful in the presentmethods and compositions include vaccines. Non-limiting examples ofantiviral vaccines include: ChronVac-C, DNA-based Therapeutic Vaccine,(Inovio/Tripep), TG4040, Therapeutic Vaccine, (Transgene), PeviPRO™,Therapeutic vaccine, (Pevion Biotect), HCV/MF59, Vaccine(s),(Chiron/Novartis), GI-5005, Therapeutic Vaccine, (Globe Immune), IC41,Therapeutic Vaccine, (Intercell), HCV/MF59 (Chiron/Novartis), GI-5005(Globe Immune), and Civacir (NABI).

Additional examples of other therapeutic agents useful in the presentmethods and compositions include anti-cancer agents. Non-limitingexamples of antiviral anti-cancer agents include: ZIO-101, Anti-LiverCancer (Arsenic), (Ziopharm Oncology), GV1001 (Heptovax), Anti-LiverCancer, (Pharmexa), PI-88, Anti-liver cancer, (Progen Industries),Nexavar (sorafenib), Anti-liver cancer, (Onyx Pharmaceuticals), andThermoDox (doxorubicin), Anti-liver cancer, (Celsion). Additionalnon-limiting examples of viral anticancer agents include CF102 (Can-FiteBioPharma), ZIO-101 (Ziopharm Oncology), GV 1001 (Heptovax) (Pharmexa),PI-88 (Progen Industries), ThermoDox (doxorubicin) (Celsion), andNexavar (sorafenib) (Onyx Pharmaceuticals).

Additional examples of other therapeutic agents useful in the presentcompositions and methods include, but are not limited to, Levovirin™(ICN Pharmaceuticals, Costa Mesa, Calif.), VP 50406™ (Viropharma,Incorporated, Exton, Pa.), ISIS 14803™ (ISIS Pharmaceuticals, Carlsbad,Calif.), Heptazyme™ (Ribozyme Pharmaceuticals, Boulder, Colo.), VX-950™(Vertex Pharmaceuticals, Cambridge, Mass.), Thymosin™ (SciClonePharmaceuticals, San Mateo, Calif.), Maxamine™ (Maxim Pharmaceuticals,San Diego, Calif.), NKB-122 (JenKen Bioscience Inc., North Carolina),mycophenolate mofetil (Hoffman-LaRoche, Nutley, N.J.).

Additional examples of other therapeutic agents useful in the presentmethods and compositions include adjunct therapeutics such asthrombopoeitin receiptor antagonists (e.g., LGD-4665, LigandPharmaceuticals Inc., and eltromobopag (Promacta), GlaxoSmithKline).

Additional examples of other therapeutic agents useful in the presentcompositions and methods include, but are not limited to: HCV/MF59, OralInterferon alpha, Viramidine, Infergen/,Consensus, JBK-122, Bavituximab(Tarvacin), Civacir, Albuferon, IL-29 (PEG-Interferon lambda), OmegaInterferon , ZADAXIN® (thymalfasin or thymosin alpha 1), NOV-205,PF-03491390 (formerly IDN-6556), Nexavar, ITMN-191, IC41, VX 950(telaprevir), R1656, MX-3253 (Celgosivir), SCH 503034 (Boceprevir),SCH900518 (Schering), Belerofon (oral), VGX-410C, ThermoDox(doxorubicin), R7128, R1626, A-831, DEBIO-025, PeviPRO™, GV1001, PYN17,PI-88, TG4040, BLX-883 (Locteron), ChronVac-R, MitoQ, GSK625433, SOV-07,IMO-2125, Alinia (nitazoxanide), LGD-4665, Z10-101, CF102, VCH-759,VCH-916, Oglufanide disodium, VX-500, TMC435350, PF-00868554, GGI-5005(Tarmogen), SPC3649 (LNA-antimiR™-122), CTS-1027, ABT-333, Eltrombopag,and ANA598.

Additional examples of other therapeutic agents useful in the presentcompositions and methods include, but are not limited to adjuncttherapeutics. Non-limiting examples include: LGD-4665, ThrombopoeitinReceptor Agonist , (Ligand Pharmaceuticals Inc.), and Eltrombopag(Promacta), Thrombopoeitin Receptor Agonist , (GlaxcoSmithKline).

The doses and dosage regimen of the other agents used in the combinationtherapies of the present invention for the treatment or prevention of aviral infection can be determined by the attending clinician, takinginto consideration the approved doses and dosage regimen in the packageinsert; the age, sex and general health of the patient; and the type andseverity of the viral infection or related disease or disorder. Whenadministered in combination, the compound(s) of the invention and theother agent(s) for treating diseases or conditions listed above can beadministered simultaneously (i.e., in the same composition or inseparate compositions one right after the other) or sequentially. Thisis particularly useful when the components of the combination are givenon different dosing schedules, e.g., one component is administered oncedaily and another every six hours, or when the preferred pharmaceuticalcompositions are different, e.g. one is a tablet and one is a capsule. Akit comprising the separate dosage forms is therefore advantageous.

Generally, a total daily dosage of the at least one compound of theinvention and the additional antiviral agent(s), when administered ascombination therapy, can range from about 0.1 to about 2000 mg per day,although variations will necessarily occur depending on the target ofthe therapy, the patient and the route of administration. In oneembodiment, the dosage is from about 10 to about 500 mg/day,administered in a single dose or in 2-4 divided doses. In anotherembodiment, the dosage is from about 1 to about 200 mg/day, administeredin a single dose or in 2-4 divided doses. In still another embodiment,the dosage is from about 1 to about 100 mg/day, administered in a singledose or in 2-4 divided doses. In yet another embodiment, the dosage isfrom about 1 to about 50 mg/day, administered in a single dose or in 2-4divided doses. In a further embodiment, the dosage is from about 1 toabout 20 mg/day, administered in a single dose or in 2-4 divided doses.In another embodiment, the dosage is from about 500 to about 1500mg/day, administered in a single dose or in 2-4 divided doses. In stillanother embodiment, the dosage is from about 500 to about 1000 mg/day,administered in a single dose or in 2-4 divided doses. In yet anotherembodiment, the dosage is from about 100 to about 500 mg/day,administered in a single dose or in 2-4 divided doses.

In one embodiment, when the other therapeutic agent is INTRON-Ainterferon alpha 2b (commercially available from Schering-Plough Corp.),this agent is administered by subcutaneous injection at 3MIU(12 mcg)/0.5mL/TIW is for 24 weeks or 48 weeks for first time treatment.

In another embodiment, when the other therapeutic agent is PEG-INTRONinterferon alpha 2b pegylated (commercially available fromSchering-Plough Corp.), this agent is administered by subcutaneousinjection at 1.5 mcg/kg/week, within a range of 40 to 150 mcg/week, forat least 24 weeks.

In another embodiment, when the other therapeutic agent is ROFERON Ainteferon alpha 2a (commercially available from Hoffmann-La Roche), thisagent is administered by subcutaneous or intramuscular injection at3MIU(11.1 mcg/mL)/TIW for at least 48 to 52 weeks, or alternatively6MIU/TIW for 12 weeks followed by 3MIU/TIW for 36 weeks.

In another embodiment, when the other therapeutic agent is PEGASUSinterferon alpha 2a pegylated (commercially available from Hoffmann-LaRoche), this agent is administered by subcutaneous injection at 180mcg/1 mL or 180 mcg/0.5 mL, once a week for at least 24 weeks.

In another embodiment, when the other therapeutic agent is INFERGENinterferon alphacon-1 (commercially available from Amgen), this agent isadministered by subcutaneous injection at 9 mcg/TIW is 24 weeks forfirst time treatment and up to 15 mcg/TIW for 24 weeks fornon-responsive or relapse treatment.

In another embodiment, when the other therapeutic agent is Ribavirin(commercially available as REBETOL ribavirin from Schering-Plough orCOPEGUS ribavirin from Hoffmann-La Roche), this agent is administered ata daily dosage of from about 600 to about 1400 mg/day for at least 24weeks.

Compositions and Administration

The compounds of the invention may be used as the neat chemical or aspart of a composition, such as a pharmaceutical composition. Forexample, when administered to a patient, the compounds of the inventioncan be administered as a component of a composition that comprises apharmaceutically acceptable carrier or vehicle. The present inventionprovides pharmaceutical compositions comprising an effective amount ofat least one compound of the invention and a pharmaceutically acceptablecarrier. In the pharmaceutical compositions and methods of the presentinvention, the active ingredients will typically be administered inadmixture with suitable carrier materials suitably selected with respectto the intended form of administration, i.e. oral tablets, capsules(either solid-filled, semi-solid filled or liquid filled), powders forconstitution, oral gels, elixirs, dispersible granules, syrups,suspensions, and the like, and consistent with conventionalpharmaceutical practices. For example, for oral administration in theform of tablets or capsules, the active drug component may be combinedwith any oral non-toxic pharmaceutically acceptable inert carrier, suchas lactose, starch, sucrose, cellulose, magnesium stearate, dicalciumphosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms)and the like. Solid fotin preparations include powders, tablets,dispersible granules, capsules, cachets and suppositories. Powders andtablets may be comprised of from about 5 to about 95 percent inventivecomposition. Tablets, powders, cachets and capsules can be used as soliddosage forms suitable for oral administration.

Moreover, when desired or needed, suitable binders, lubricants,disintegrating agents and coloring agents may also be incorporated inthe mixture. Suitable binders include starch, gelatin, natural sugars,corn sweeteners, natural and synthetic gums such as acacia, sodiumalginate, carboxymethylcellulose, polyethylene glycol and waxes. Amongthe lubricants there may be mentioned for use in these dosage forms,boric acid, sodium benzoate, sodium acetate, sodium chloride, and thelike. Disintegrants include starch, methylcellulose, guar gum and thelike. Sweetening and flavoring agents and preservatives may also beincluded where appropriate.

Liquid form preparations include solutions, suspensions and emulsionsand may include water or water-propylene glycol solutions for parenteralinjection.

Liquid form preparations may also include solutions for intranasaladministration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Additionally, the compositions of the present invention may beformulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimize the therapeutic effects, i.e. anti-inflammatory activity andthe like. Suitable dosage forms for sustained release include layeredtablets containing layers of varying disintegration rates or controlledrelease polymeric matrices impregnated with the active components andshaped in tablet form or capsules containing such impregnated orencapsulated porous polymeric matrices.

In one embodiment, the one or more compounds of the invention are in aform suitable for oral administration.

In another embodiment, the one or more compounds of the invention are ina form suitable for intravenous administration.

In another embodiment, the one or more compounds of the invention are ina form suitable for topical administration.

In another embodiment, the one or more compounds of the invention are ina form suitable for sublingual administration.

In one embodiment, a pharmaceutical preparation comprising at least onecompound of the invention is formulated in a unit dosage form. In suchform, the preparation is subdivided into unit doses containingappropriate quantities of the active component, e.g., an effectiveamount to achieve the desired purpose.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentcompositions can contain, in one embodiment, from about 0.1% to about99% of the compound(s) of the invention by weight or volume. In variousembodiments, the present compositions can contain, in one embodiment,from about 1% to about 70% or from about 5% to about 60% of thecompound(s) of the invention by weight or volume.

The quantity of compound(s) of the invention in a unit dose ofpreparation may be varied or adjusted from about 0.1 mg to about 2000mg. In various embodiment, the quantity is from about 1 mg to about 2000mg, 100 mg to about 200 mg, 500 mg to about 2000 mg, 100 mg to about1000 mg, and 1 mg to about 500 mg.

For convenience, the total daily dosage may be divided and administeredin portions during the day if desired. In one embodiment, the dailydosage is administered in one portion. In another embodiment, the totaldaily dosage is administered in two divided doses over a 24 hour period.In another embodiment, the total daily dosage is administered in threedivided doses over a 24 hour period. In still another embodiment, thetotal daily dosage is administered in four divided doses over a 24 hourperiod.

The amount and frequency of administration of the compound(s) of theinvention will be determined according to the judgment of the attendingclinician considering such factors as age, condition and size of thepatient as well as severity of the symptoms being treated. Generally, atotal daily dosage of the compound(s) of the invention range from about0.1 to about 2000 mg per day, although variations will necessarily occurdepending on the target of the therapy, the patient and the route ofadministration. In one embodiment, the dosage is from about 1 to about200 mg/day, administered in a single dose or in 2-4 divided doses. Inanother embodiment, the dosage is from about 10 to about 2000 mg/day,administered in a single dose or in 2-4 divided doses. In anotherembodiment, the dosage is from about 100 to about 2000 mg/day,administered in a single dose or in 2-4 divided doses. In still anotherembodiment, the dosage is from about 500 to about 2000 mg/day,administered in a single dose or in 2-4 divided doses.

The compositions of the invention can further comprise one or moreadditional therapeutic agents, selected from those described above.Accordingly, in one embodiment, the present invention providescompositions comprising: (i) at least one compound of the invention or apharmaceutically acceptable salt, solvate, ester or prodrug thereof;(ii) one or more additional therapeutic agents that are not a compoundof the invention; and (iii) a pharmaceutically acceptable carrier,wherein the amounts in the composition are together effective to treat aviral infection or a virus-related disorder.

Kits

In another embodiment, the present invention provides a kit comprising atherapeutically effective amount of at least one compound of theinvention, or a pharmaceutically acceptable salt, solvate, ester,isomer, tautomer, or prodrug of said compound and a pharmaceuticallyacceptable carrier, vehicle or diluent.

In another aspect the present invention provides a kit comprising anamount of at least one compound of the invention, or a pharmaceuticallyacceptable salt, solvate, ester, isomer, tautomer, or prodrug of saidcompound and an amount of at least one additional therapeutic agentlisted above, wherein the amounts of the two or more ingredients resultin a desired therapeutic effect.

The present invention is not to be limited by the specific embodimentsdisclosed in the examples that are intended as illustrations of a fewaspects of the invention and any embodiments that are functionallyequivalent are within the scope of this invention. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparant to those skilled in the art and are intendedto fall within the scope of the appended claims.

A number of references have been cited herein. The entire disclosures ofsuch references are incorporated herein by reference.

1. A compound having the general structure shown in Formula (A):

(A), or a pharmaceutically acceptable salt thereof, wherein each of R, R¹, X, Y, Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁸, R¹⁹, R²², R²³, and n are selected independently and wherein: R²² and R²³ are each independently selected from H, alkyl, and cycloalkyl; R is selected from H, alkyl, aryl, heteroaryl, cycloalkyl, aryl-fused cycloalkyl, heteroaryl-fused cycloalkyl, cycloalkenyl, aryl-fused cycloalkenyl, heteroaryl-fused cycloalkenyl, heterocycloalkyl, aryl-fused heterocycloalkyl, and heteroaryl-fused heterocycloalkyl, wherein each of said alkyl, said aryl, said heteroaryl, said cycloalkyl, said aryl-fused cycloalkyl, said heteroaryl-fused cycloalkyl, said cycloalkenyl, said aryl-fused cycloalkenyl, said heteroaryl-fused cycloalkenyl, said heterocycloalkyl, said aryl-fused heterocycloalkyl, and said heteroaryl-fused heterocycloalkyl, is unsubstituted or optionally independently substituted with from one to three substituents, which are the same or different, each substituent being independently selected from halo, —OH, —CN, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heterohaloalkyl, -alkyl-OH, —O-alkyl, —O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl, —S-alkyl-aryl, heteroaryl, heteroarylalkyl-, —O-heteroaryl, —S-heteroaryl, —O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, heterocycloalkylalkyl-, —C(O)-alkyl, —C(O)-haloalkyl, —C(O)-cycloalkyl, —C(O)-heterocycloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —C(O)O-haloalkyl, —C(O)O-cycloalkyl, —C(O)O-heterocycloalkyl, —OC(O)-alkyl, —OC(O)-haloalkyl, —OC(O)-cycloalkyl, —OC(O)-heterocycloalkyl, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —OC(O)NH₂, —CO(O)NHR¹⁰, —CO(O)NR¹⁰R¹¹, —NH₂, —NHR¹⁰, —NR¹⁰R¹¹, —NO₂, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰, —S(O)₂NH₂, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)₂R¹⁰, substituted aryl, and substituted heteroaryl, wherein each of said substituted aryl and said substituted heteroaryl independently contains from one to five substituents, which may be the same or different, each substituent being independently selected from halo, alkyl, —O-alkyl, and —C(O)Oalkyl; X and Y are each independently selected from N and CH, with the proviso that at least one of X or Y is N; Z═H, halo, —OH, —SH, —CN, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterohaloalkyl, —S-alkyl, —O-alkyl, —O-aryl, —O-heteroaryl, cycloalkyl, aryl, heteroaryl, —NH₂, —NHR¹², and —NR¹²R¹³; R¹ is selected from H, halo, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, heteroaryl, —OH, —O-alkyl, —O-aryl, —O-heteroalkyl, —O-heteroaryl, —SH, —S-alkyl, —S-aryl, —S-heteroalkyl, —S-heteroaryl, —NH₂, —NHR¹⁴, —NR¹⁴R¹⁵, —NO₂, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰; R² (when R² is not joined with R⁹) is selected from H and alkyl; n=0, 1, or 2; R³ is selected from H, -alkyl, -alkenyl, alkynyl, aryl, heteroaryl, and cycloalkyl, wherein each of said -alkyl, said -alkenyl, said alkynyl, said aryl, said heteroaryl, and said cycloalkyl, is unsubstituted or optionally independently substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, —O-alkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl; R⁴ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰, wherein each of said -alkyl, said -alkenyl, said alkynyl, said aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally independently substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl; R⁵ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰, wherein each of said -alkyl, said -alkenyl, said alkynyl, said aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally independently substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl; or, alternatively, R⁴ and R⁵ are taken together with the carbon atom to which they are shown attached to form a 3- to 7-membered, saturated or partially unsaturated, spirocycloalkyl ring containing from 0 to 3 spiro ring heteroatoms selected from O, N, and S; R⁶ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰, wherein each of said -alkyl, said -alkenyl, said alkynyl, said aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally independently substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl; or, alternatively, R⁵ and R⁶ are taken together to form a double bond; R⁷ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰, wherein each of said -alkyl, said -alkenyl, said alkynyl, said aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally independently substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl; or, alternatively, R⁶ and R⁷ are taken together with the carbon atom to which they are shown attached to form a 3- to 7-membered, saturated or partially unsaturated, spirocycloalkyl ring containing from 0 to 3 spiro ring heteroatoms selected from O, N, and S; R⁸ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰, wherein each of said -alkyl, said -alkenyl, said alkynyl, said aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally independently substituted with from one to five substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-cycloalkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —O(C)O—N(R¹⁰)R¹¹, —O(C)O—NHR¹¹, —O(C)O—NH₂, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, —S(O)₂R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, —CN, —NH₂, —NHR¹⁶, and —NR¹⁶R¹⁷, —N(R¹⁰)S(O)₂R¹⁰, —NHS(O)₂R¹⁰, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl; R⁹ is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰, C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰, wherein each of said -alkyl, said -alkenyl, said alkynyl, said aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally independently substituted with from one to five substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-cycloalkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —O(C)O—N(R¹⁰R¹¹, —O(C)O—NHR¹¹, —O(C)O—NH₂, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, —S(O)₂R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, —CN, —NH₂, —NHR¹⁶, and —NR¹⁶R¹⁷, —N(R¹⁰)S(O)₂R¹⁰, —NHS(O)₂R¹⁰, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl; or, alternatively, R⁸ and R⁹ are taken together with the carbon atom to which they are shown attached to form a 3- to 7-membered, saturated or partially unsaturated, spirocycloalkyl ring containing from 0 to 3 spiro ring heteroatoms selected from O, N, and S; each R¹⁸ (when present) is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰, wherein each of said -alkyl, said -alkenyl, said alkynyl, said aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally independently substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl; each R¹⁹ (when present) is selected from H, —OH, halo, -alkyl, -alkenyl, alkynyl, azido, aryl, heteroaryl, —O-alkyl, —O-alkenyl, —OC(O)-alkyl, —SH, —S-alkyl, —NH₂, —NO₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)NHR¹⁰, —S(O)NR¹⁰R¹¹, —S(O)R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, and —S(O)₂R¹⁰, wherein each of said -alkyl, said -alkenyl, said alkynyl, said aryl, said heteroaryl, said —O-alkyl, said —O-alkenyl, said —OC(O)-alkyl, and said —S-alkyl is unsubstituted or optionally independently substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl; or, alternatively, n is 1 and R¹⁸ and R¹⁹ are taken together with the carbon atom to which they are attached to form a 3- to 7-membered, saturated or partially unsaturated, spirocycloalkyl ring containing from 0 to 3 spiro ring heteroatoms selected from O, N, and S; or, alternatively, R⁴ and R⁷, together with the carbon atoms to which they are shown attached, form a moiety (1C):

wherein R²⁰ and R²¹ are each independently selected from H, alkyl, and heteroalkyl and wherein R⁵ and R⁶ are defined above, with the proviso that when R⁴ and R⁷ form a moiety (1C), then R⁵ and R⁶ are not taken together to form a double bond; or, alternatively, R⁴ and R⁷, together with the carbon atoms to which they are shown attached, form a moiety (1D):

wherein R⁵ and R⁶ are as defined above; or, alternatively, R⁴ and R⁷, together with the carbon atoms to which they are shown attached, form a moiety (1E):

wherein R⁵ and R⁶ are as defined above; each R¹⁰ is independently selected from alkyl, alkenyl, haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl, -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl, —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; each R¹¹ is independently selected from alkyl, alkenyl, haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl, -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl, —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; or, alternatively, R¹⁰ and R¹¹ are linked together with the nitrogen to which they are attached to form an unsubstituted or substituted 4- or 6-membered heterocycloalkyl; each R¹² is independently selected from alkyl, alkenyl, haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl, -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl, —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; each R¹³ is independently selected from alkyl, alkenyl, haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl, -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl, —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; or, alternatively, R¹² and R¹³ are linked together with the nitrogen to which they are attached to form an unsubstituted or substituted 4- to 6-membered heterocycloalkyl; each R¹⁴ is independently selected from alkyl, alkoxy, alkenyl, haloalkyl, heteroalkyl, heterohaloalkyl, alkylamino, alkylthio, heteroalkenyl, haloalkenyl, —S(O)₂-alkyl, -alkyl-OH, -alkyl-O-Acyl, —C(O)Oalkyl, —C(O)alkyl, cycloalkyl, cycloalkyl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, heterocycloalkenyl, heterocycloalkenyl-alkyl-, aryl, aryl-alkyl-, heteroaryl, and heteroaryl-alkyl-, wherein each said alkyl, each said alkoxy, each said alkenyl, each said haloalkyl, each said heteroalkyl, each said heterohaloalkyl, each said alkylamino, each said alkylthio, each said heteroalkenyl, each said haloalkenyl, each said —S(O)₂-alkyl, each said -alkyl-OH, each said -alkyl-O-Acyl, each said —C(O)Oalkyl, each said —C(O)alkyl, each said cycloalkyl, each said cycloalkyl-alkyl-, each said heterocycloalkyl, each said heterocycloalkyl-alkyl-, each said heterocycloalkenyl, each said heterocycloalkenyl-alkyl-, each said aryl, each said aryl-alkyl-, each said heteroaryl, and each said heteroaryl-alkyl-, is unsubstituted or optionally independently substituted with from one to three substituent, which can be the same or different, each substitutent being independently selected from —OH, halo, —NH₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)₂alkyl, —S(O)₂aryl, alkyl, alkoxy, haloalkyl, haloalkoxy, heteroalkyl, heteroalkyl, heterohaloalkyl, aryl, cycloalkyl, and heterocycloalkyl; each R¹⁵ is independently selected from alkyl, alkoxy, alkenyl, haloalkyl, heteroalkyl, heterohaloalkyl, alkylamino, alkylthio, heteroalkenyl, haloalkenyl, —S(O)₂-alkyl, -alkyl-OH, -alkyl-O-Acyl, —C(O)Oalkyl, —C(O)alkyl, cycloalkyl, cycloalkyl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, heterocycloalkenyl, heterocycloalkenyl-alkyl-, aryl, aryl-alkyl-, heteroaryl, and heteroaryl-alkyl-, wherein each said alkyl, each said alkoxy, each said alkenyl, each said haloalkyl, each said heteroalkyl, each said heterohaloalkyl, each said alkylamino, each said alkylthio, each said heteroalkenyl, each said haloalkenyl, each said —S(O)₂-alkyl, each said -alkyl-OH, each said -alkyl-O-Acyl, each said —C(O)Oalkyl, each said —C(O)alkyl, each said cycloalkyl, each said cycloalkyl-alkyl-, each said heterocycloalkyl, each said heterocycloalkyl-alkyl-, each said heterocycloalkenyl, each said heterocycloalkenyl-alkyl-, each said aryl, each said aryl-alkyl-, each said heteroaryl, and each said heteroaryl-alkyl-, is unsubstituted or optionally independently substituted with from one to three substituent, which can be the same or different, each substitutent being independently selected from —OH, halo, —NH₂, —NHR¹⁰, —NR¹⁰R¹¹, —C(O)OH, —C(O)OR¹⁰, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —S(O)₂alkyl, —S(O)₂aryl, alkyl, alkoxy, haloalkyl, haloalkoxy, heteroalkyl, heteroalkyl, heterohaloalkyl, aryl, cycloalkyl, and heterocycloalkyl; or, alternatively, R¹⁴ and R¹⁵ are linked together with the nitrogen to which they are attached to form an unsubstituted or substituted 4- to 6-membered heterocycloalkyl; each R¹⁶ is independently selected from alkyl, alkenyl, haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl, -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl, —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; and each R¹⁷ is independently selected from alkyl, alkenyl, haloalkyl, heteroalkyl, heterohaloalkyl, —S(O)₂-alkyl, -alkyl-OH, —C(O)Oalkyl, —C(O)alkyl, —C(O)NHalkyl, —C(O)N(alkyl)₂, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; or, alternatively, R¹⁶ and R¹⁷ are linked together with the nitrogen to which they are attached to form an unsubstituted or substituted 4- or 6-membered heterocycloalkyl.
 2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: R²² and R²³ are each H; R is selected from aryl, heteroaryl, benzo-fused heteroaryl, cycloalkyl, cycloalkenyl, benzo-fused cycloalkyl, benzo-fused cycloalkenyl, heterocycloalkyl, and benzo-fused heterocycloalkyl, wherein each of said alkyl, said aryl, said heteroaryl, said benzo-fused heteroaryl, said cycloalkyl, said cycloalkenyl, said heterocycloalkyl, said heterocycloaklenyl, and said benzo-fused heterocycloalkyl is unsubstituted or optionally independently substituted with from one to five substituents, which are the same or different, each substituent being independently selected from halo, —OH, —CN, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, heterohaloalkyl, -alkyl-OH, —O-alkyl, —O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl, —S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl, —O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —C(O)ONH₂, —C(O)ONHR¹⁰, —C(O)ONR¹⁰R¹¹, —NH₂, —NHR¹⁰, —NR¹⁰R¹¹, —NO₂, substituted aryl, and substituted heteroaryl, wherein each of said substituted aryl and said substituted heteroaryl independently contains from one to three substituents, which may be the same or different, each substituent being independently selected from halo, alkyl, —O-alkyl, and —C(O)Oalkyl; R¹ is selected from —NH₂, —NHR¹⁴, and —NR¹⁴R¹⁵; and Z is selected from H, halo, alkyl, —OH, haloalkyl, and cycloalkyl.
 3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: X is N; Y is N; R²² and R²³ are each H; R is selected from the group consisting of: (a) an unsubstituted or substituted monocyclic aryl moiety or an unsubstituted or substituted heteroaryl moiety selected from the group consisting of:

wherein the wavy line represents the point of attachment of R to the rest of the molecule, and wherein each of R_(a), R_(b), R_(c), R_(d), and R_(e), is independently selected from H, halo, —OH, —CN, alkyl, cycloalkyl, haloalkyl, -alkyl-OH, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl, —S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl, —O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-alkyl, —C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —C(O)ONH₂, —C(O)ONHR¹⁰, —C(O)ONR¹⁰R¹¹, —NH₂, —NHR¹⁰, —NR¹⁰R¹¹, —NO₂, substituted aryl, and substituted heteroaryl, wherein each of said substituted aryl and said substituted heteroaryl independently contains from one to three substituents, which may be the same or different, each substituent being independently selected from halo, alkyl, —O-alkyl, and —C(O)Oalkyl, and (b) an unsubstituted or an substituted bicyclic heteroaryl moiety selected from the group consisting of:

wherein the wavy line represents the point of attachment of R to the rest of the molecule, and wherein each of R_(a), R_(b), R_(c), R_(d), and R_(e), is independently selected from H, halo, —OH, —CN, alkyl, cycloalkyl, haloalkyl, -alkyl-OH, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl, —S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl, —O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-alkyl, —C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —C(O)ONH₂, —C(O)ONHR¹⁰, —C(O)ONR¹⁰R¹¹, —NH₂, —NHR¹⁰, —NR¹⁰R¹¹, —NO₂, substituted aryl, and substituted heteroaryl, wherein each of said substituted aryl and said substituted heteroaryl independently contains from one to three substituents, which may be the same or different, each substituent being independently selected from halo, alkyl, —O-alkyl, and —C(O)Oalkyl; R¹ is selected from the group consisting of: (a) —NH₂,

wherein the wavy line represents the point of attachment of R¹ to the rest of the molecule, and wherein each R_(aa) is independently selected from haloalkyl, R_(ab) is selected from OH, OAc, and O-alkyl O-haloalkyl , —NH₂, —NHalkyl, and —N(alkyl)₂,

wherein the wavy line represents the point of attachment of R¹ to the rest of the molecule, and wherein R_(af) is selected from H and acetyl,

wherein the wavy line represents the point of attachment of R¹ to the rest of the molecule, and wherein each of R_(a), R_(b), R_(c), R_(d), and R_(e), is independently selected from H, halo, —OH, —CN, alkyl, cycloalkyl, haloalkyl, -alkyl-OH, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl, —S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl, —O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-alkyl, —C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —C(O)ONH₂, —C(O)ONHR¹⁰, —C(O)ONR¹⁰R¹¹, —NH₂, —NHR¹⁰, —NR¹⁰R¹¹, —NO₂, substituted aryl, and substituted heteroaryl, wherein each of said substituted aryl and said substituted heteroaryl independently contains from one to three substituents, which may be the same or different, each substituent being independently selected from halo, alkyl, —O-alkyl, and —C(O)Oalkyl, and wherein each R_(ad) R_(ad) and each R_(ae) is independently selected from alkyl and haloalkyl,

wherein the wavy line represents the point of attachment of R¹ to the rest of the molecule, and wherein each R_(aa) is independently selected from haloalkyl, R_(ab) is selected from OH, OAc, and O-alkyl, —O-haloalkyl , —NH₂, —NHalkyl, and —N(alkyl)₂,

wherein the wavy line represents the point of attachment of R¹ to the rest of the molecule, and wherein R_(af) is selected from H and acetyl,

wherein the wavy line represents the point of attachment of R¹ to the rest of the molecule, and wherein each of R_(a), R_(b), R_(c), R_(d), and R_(e), is independently selected from H, halo, —OH, —CN, alkyl, cycloalkyl, haloalkyl, -alkyl-OH, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-haloalkyl, —O-alkyl-OH, aryl, —O-aryl, —S-aryl, —O-alkyl-aryl, —S-alkyl-aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl, —O-alkyl-heteroaryl, —S-alkyl-heteroaryl, heterocycloalkyl, —C(O)-alkyl, —C(O)-haloalkyl, —C(O)H, —C(O)OH, —C(O)O-alkyl, —OC(O)-alkyl, —C(O)NH₂, —C(O)NHR¹⁰, —C(O)NR¹⁰R¹¹, —C(O)ONH₂, —C(O)ONHR¹⁰, —C(O)ONR¹⁰R¹¹, —NH₂, —NHR¹⁰, —NR¹⁰R¹¹, —NO₂, substituted aryl, and substituted heteroaryl, wherein each of said substituted aryl and said substituted heteroaryl independently contains from one to three substituents, which may be the same or different, each substituent being independently selected from halo, alkyl, —O-alkyl, and —C(O)Oalkyl, and wherein each R_(ad) R_(ad) and each R_(ae) is independently selected from alkyl and haloalkyl, and

wherein X is selected from O, NH, and NMe; and Z is selected from the group consisting of H, halo, —OH, —SH, —CN, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterohaloalkyl, —S-alkyl, —O-alkyl, —O-aryl, —O-heteroaryl, cycloalkyl, aryl, heteroaryl, —NH₂, —NHR¹², and —NR¹²R¹³.
 4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, said compound having the general structure shown in Formula (I.a):

wherein each of R, R¹, X, Y, Z, R², R⁴, R⁵, R⁷, and R⁹ is selected independently and defined in claim
 1. 5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: n is 1; R² is H; R⁴ and R⁷ are each independently selected from H and OH; R⁵ is selected from H, halo, and alkyl; and R⁹ is alkyl, wherein said alkyl is unsubstituted or substituted with from one to five substituents, which can be the same or different, each substituent being independently selected from halo, —OH, alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, —O-alkyl, —O-cycloalkyl, —O-alkenyl, —O-haloalkyl, —O-haloalkenyl, —OC(O)-alkyl, —OC(O)-alkenyl, —OC(O)-haloalkyl, —OC(O)-haloalkenyl, —O(C)O—NHR¹⁰, —O(C)O—N(R¹⁰)R¹¹, —C(O)O-alkyl, —C(O)O-alkenyl, —C(O)O-haloalkyl, —C(O)O-haloalkenyl, —S(O)₂R¹⁰, —S(O)₂NHR¹⁰, —S(O)₂NR¹⁰R¹¹, —CN, —NH₂, —NHR¹⁶, and —NR¹⁶R¹⁷, —NHS(O)₂R¹⁰, —N(R¹⁰)S(O)₂R¹⁰, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl.
 6. A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein: n is 1; R² is H; R⁴ is OH; R⁷ is OH; R⁵ is H; and R⁹ is alkyl, wherein said alkyl is unsubstituted or substituted with from one to five groups independently selected from —OH, halo, —CN, —NH₂, —NHR¹⁶, —NR¹⁶R¹⁷, —NHS(O)₂R¹⁰, —N(R¹⁰)S(O)₂R¹⁰, -Oalkyl, -Ocycloalkyl, —O-alkyl-cycloalkyl, —OC(O)-alkyl, —O(C)O—NHR¹⁰, —O(C)O—N(R¹⁰)R¹¹, —C(O)O-alkyl, —S(O)₂R¹⁰, —SR¹⁰, —S(O)₂NHR¹⁰, and —S(O)₂NR¹⁰R¹¹.
 7. A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein: n is 1; R² is H; R⁴ is OH; R⁷ is OH; R⁵ is —CH₃, and and R⁹ is methyl, wherein said methyl is unsubstituted or substituted with from one to three groups independently selected from —OH, halo, alkyl, —CN, —NH₂, —NHR¹⁶, —NR¹⁶R¹⁷, —NHS(O)₂R¹⁰, —N(R¹⁰)S(O)₂R¹⁰, -Oalkyl, -Ocycloalkyl, —O-alkyl-cycloalkyl, —OC(O)-alkyl, —O(C)O—NHR¹⁰, —O(C)O—N(R¹⁰)R¹¹, —C(O)O-alkyl, —S(O)₂R¹⁰, —SR¹⁰, —S(O)₂NHR¹⁰, and —S(O)₂NR¹⁰R¹¹.
 8. A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein: X and Y are each N; R is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted benzo-fused heteroaryl, each of said substituents being independently selected from the group consisting of alkyl, cycloalkyl, and —O-alkyl; Z is selected from H, halo, alkyl, fluoroalkyl, cyclopropyl, and —NH₂; R¹ is selected from —NH₂, —NHR¹⁴, and —NR¹⁴R¹⁵; and R² is selected from H.
 9. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, said compound having the general structure shown in Formula (I.a.10.j):

wherein: CB is a moiety selected from the group consisting of:

wherein each R¹⁰ is independently selected from the group consisting of methyl, ethyl, and cyclopropyl.
 10. A compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein: X is N; Y is N; R² is H; Z is selected from the group consisting of H, methyl, and chloro; R is unsubstituted phenyl or phenyl substituted with from 1 to 4 substituents independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, halo, —CN, —NH₂, and —NO₂, or, alternatively, R is unsubstituted heteroaryl or heteroaryl substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, alkoxy, cycloalkyl, halo, —CN, —NH₂, and —NO₂; and R¹ is selected from the group consisting of —NH₂, —NHR¹⁴, and —NR¹⁴R¹⁵.
 11. A compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein: X is N; Y is N; R² is H; Z is selected from the group consisting of H, methyl, and chloro; R is unsubstituted phenyl or phenyl substituted with from 1 to 4 substituents independently selected from the group consisting of alkyl, alkoxy, halo, —CN, —NH₂, and —NO₂, or, alternatively, R is unsubstituted pyridyl or pyridyl substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, alkoxy, halo, —CN, —NH₂, and —NO₂; R¹ is —NH₂; and CB is a moiety having a formula:


12. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, said compound having the general structure shown in Formula (I.C):

wherein each of R, R¹, X, Y, Z, R², R³, R⁵, R⁶, R⁸, R⁹, R¹⁸, R¹⁹, R²⁰, R²¹, and n is selected independently and defined in claim 1, with the proviso that R⁵ and R⁶ are not taken together to form a double bond.
 13. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, said compound having the general structure shown in Formula (I.D):

wherein each of R, R¹, X, Y, Z, R², R³, R⁵, R⁶, R⁸, R⁹, R¹⁸, and R¹⁹, and n is selected independently and defined in claim
 1. 14. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, said compound having the general structure shown in Formula (I.E):

wherein each of R, R¹, X, Y, Z, R², R³, R⁵, R⁶, R⁸, R⁹, R¹⁸, and R¹⁹, and n is selected independently and defined in Formula (I).
 15. A compound, or a pharmaceutically acceptable salt thereof, said compound having the general structure shown in Formula (II):

wherein each of R, R¹, X, Y, Z, R³, R⁴, R⁵, R⁶, R⁷, and R⁸ is selected independently and defined in claim
 1. 16. A compound selected from the group consisting of: Compd # Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

or a pharmaceutically acceptable salt thereof.
 17. A pharmaceutical composition comprising at least one compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 18. A pharmaceutical composition according to claim 17, further comprising at least one additional therapeutic agent selected from the group consisting of: an HCV polymerase inhibitor, an interferon, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a viral protease inhibitor, a virion production inhibitor, an immunosuppressive agent, an antiviral antibody, a CYP-450 inhibitor, an antiviral booster, and an antiviral sensitizer.
 19. A method of treating a viral infection or a virus-related disorder comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound according to claim
 1. 20. A method according to claim 19, wherein said viral infection or virus-related disorder is an HCV infection.
 21. A method according to claim 19, further comprising administering a therapeutically effective amount of at least one additional therapeutic agent useful for treating a viral infection or a virus-related disorder, wherein said at least one additional therapeutic agent is selected from the group consisting of: an HCV polymerase inhibitor, an interferon, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a viral protease inhibitor, a virion production inhibitor, an immunosuppressive agent, an antiviral antibody, a CYP-450 inhibitor, an antiviral booster, and an antiviral sensitizer. 